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Embryology – Study Notes – 2016/2017

Basic Principles of Development

Fertilization produces a zygote.


Conception – fusion of sperm and egg.
Conceptus – the product of conception including embryo/fetus and fetal membranes
Embryonic development – divided into embryonic and fetal period.
o Embryonic period – first zygote cleavage through to establishment of major organ systems.
o Fetal period – growth and organ refinement up to point of birth.
Major events in embryonic development:
o Proliferation – cellular mitosis
o Differentiation – specialization of cells from less specialized ones

Signalling mechanisms:
 Cell-surface receptor proteins
 Intracellular signalling proteins
 Target proteins

Cells receive many signals, and sorts them out by expressing certain adhesion molecules/receptors.

Responses to cell signalling:


 Change morphology
 Divide
 Differentiate
 Apoptosis

Types of Signalling:
 Paracrine Signalling: short range, signalling molecule reaches target cell by diffusion, signalling molecule can be immobilized
by ECM to ensure signal is localized for nearby cells.
 Contact-dependent Signalling: short range, cell giving off signal must b e in contact with target cell. A molecule (membrane
protein) on cell binds to specific receptor on adjacent cell OR a signal (metabolite/ion) is transmitted to adjacent cell
cytoplasm via gap junctions.
 Autocrine Signalling: short range, cells send signal to a similar cell type or to themselves, helps a group of cells to follow a
common developmental fate.
 Synaptic Signalling: long range (distance) signalling via neurons.
 Endocrine Signalling: long range, signal delivered via diffusion or blood, slow acting but long lived, small amount of
signalling molecules required to induce a widespread & sustained response.

Signalling Networks:
 Feedback Loops:
o +ve: downstream element stimulates
upstream element
o –ve: downstream element inhibits
upstream element
 Feedforward Relay: upstream element
stimulates an immediate target and a
downstream element at same time – AMPLIFYING the effect.
 Crosstalk:
o Stimulatory: element of 1 pathway stimulates element of a 2nd pathway
o Inhibitory: element of 1 pathway inhibits element of 2nd pathway
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Differentiation:
 Commitment: cell specification (reversible), cell determination
(irreversible – fate of cell determined)
 Is a gradual process of lineage decisions, regulated by gene
expression.
 Induction: cell signalling induces changes in cell gene expression
& thus differentiation
o Induction only happens when the cell is competent (cell
needs correct receptors for signalling molecules).
o Signalling molecules/receptors are present for a limited window of time – CRITICAL period.

Potency:
 Totipotency: zygote and blastomeres possess equal potency – can form all cells
 Pluripotency: cells more restricted in developmental potential
o eg. ICM cells can form embryo proper, but cannot form extra-embryonic tissues.
 Multipotency: cells have several developmental potentials
o Eg. After gastrulation cells are multipotent
 Unipotency: germ layer cells give rise to tissue-specific cells that produce single types of differentiated cells.
o Eg. Satellite cells can divide to form ONLY skeletal muscle cells.
 Terminal Differentiation: cells fully matured and cannot divide/differentiate further.
o Eg. Skeletal muscle cells

Patterning: embryonic cells organize into tissues/organs – driven by gene expression & morphogens (gradients of signalling
molecules). Is differentiation on a tissue scale. Is a sequential process
 Homeobox Genes (fruit fly): for cranial-caudal patterning: 3’ end of chromosome expressed 1st in development and pattern
anterior body parts, 5’ end of chromosome expressed later and pattern po sterior body parts.
 Homeobox Genes (mammals): expressed in overlapping
patterns/combinations along body axis and provide
POSITIONAL identify.
 Hox 5 – cervical vertebrae
o Proximo-distal patterning:
 Hox 9/10 – proximal limb buds
 Hox 13 – distal limb buds
 Dorso-ventral patterning of nervous system results from
TGF-beta & Shh. See figure.

Morphogenesis: mechanism where tissues/organs are shaped. Tube


formation, sheet formation, clumping and dispersion of cells due to
changes in cell adhesion.

Neural Tube formation:


 Neural plate expresses N-cadherins – that cause tube formation.
 Epidermis beside neural plate expresses E-cadherins – that do
not cause tube formation

Early Embryonic Development I

 Cleavage: mitotic cell divisions in embryo. Cells of divisions called blastomeres. Rapid cellularity, no growth, shape
maintained, initially synchronous.
o Holoblastic: furrow completely cuts through embryo, occurs in embryos w/ little -moderate yolk (amphibians,
mammals) – can be unequal or equal.
 Radial – blastomeres one on top of another (echinoderms)
 Bilateral – furrow establishes plane of symmetry (tunicates)
 Spiral – blastomeres offset from one another (molluscs)
 Rotational – blastomeres at right angles to one another (mammals)
o Meroblastic – imcomplete cleavage divisions, occurs in embryos with lots of yolk (fish, reptiles).

Mammals have asynchronous, rotational, holoblastic divisions.


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Pre-implantation development: before embryo implants into uterus.
 Zona Pellucida: glycoprotein ECM surrounding oocyte and early embryo.
 Zygote in Oviduct
 Blastocyst in Uterus
 Activation of Embryonic Genome: happens during cleavage stage (~ 8-cell stage) cellular machinery becomes that of embryo
and maternal transcripts/proteins are degraded.

Event I – Compaction
 At 8-cell stage cells huddle closely to form a ball due to blastomere polarization
 Outer blastomeres express Cdx2 and Eomes and inner blastomeres express Oct4.
 Outside cells (blastomeres) form tight seal w/ tight junctions, desmosomes, and adherans junctions. These cells will become
trophectoderm then trophoblast.
 Inside cells connect via gap junction and will become the inner cell mass (ICM).
 E-cadherin also needed for compaction – blocking its function prevents compaction.
 16-cell stage is a Morula.

Event II – Cavitation
 Morula undergoes an influx of H2 O 1st forming vesicles, which coalesce to form a blastocoel (fluid filled cavity ) forming the
early blastocyst.
 Na/K-ATPase is primary driver – pumps 3 Na+ into cavity, and 2K+ out- creating osmotic gradient for water to flow into
blastocoel.

Event III – Blastocyst Expansion


 Na/K-ATPase is primary driver & tight permeability required
o Ouabain inhibits enzyme and expansion
o Disrupted by drugs that breakdown actin cytoskeleton of Ca2+ requiring adhesion molecules (cadherins)
 ICM and trophectoderm differentiate in this stage
 Blastocyst undergoes contractions that “tests” strength of ZP.
 Results in blastocyst hatching & ICM differentiation into hypoblast and epiblast (bilaminar disk) & the establishment of
embryonic axes (craniocaudal, dorsoventral, R/L).

Event IV - Hatching
 Growth/fluid accumulation in blastocoel
 Production of enzymes (proteases ie. Strypsin) by trophectoderm to breakdown ZP
 Contraction of blastocyst
 Hatching results in a free-floating embryo in uterus lumen.

Embryo Transfer:
1. Synchronization of recipients with donors
2. Superovulation of donor – inject w/ gonadotropins to induce follicle development & ovulation
3. Inseminate donor w/ semen from genetically superior bull – use pipette & go past cervix and deposit into uterine horn
4. Recovery and identification of viable embryo – flush uterine horns w/ foley catheter and collect embryo via syringe
5. Transfer viable embryo into synchronized recipient – deposit into uterine horn

Why do embryo transfer?


 Increase # of offspring
 Circumvent seasonal reproduction
 Prevention of endangered species
 Enhance genetic diversity
 Cryopreservation

Embryo Quality: blastocyst must be able to pulse/expansion/contraction OR morulae must have a clean surface & show compaction .

Early Embryonic Development II

Functions of Zona Pellucida: protects embryo from contractions of ov iduct, helps break itself down (proteases), protects embryo from
infection (viruses).
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Hypoblast: flattened cells facing blastocoel that form a sheet that lines epiblast and
trophectoderm – it is an epithelium & eventually forms part of yolk sac. GATA-6 expression
essential. Hypoblast secretes basement membrane b/w the epiblast and hypoblast .

Epiblast: cells of ICM that are multilayered. Nanog expression essential for development.

Embryonic disk: Rauber’s layer of trophectoderm cells overlying the epiblast disintegrate
exposing it. The epiblast becomes ovoid and with the hypoblast forms the embryonic disk.

Pre-attachment vs Attachment
 Long Pre-attachment Period: most domestic animals, extra-embryonic membrane
develops into amnion, allantois, and chorion.
 Short Pre-attachment Period: primates, blastocyst implants quickly after entering
uterus, extra-embryonic membrane development occurs after implantation.

Expansion: as embryonic disc forms, blastocyst expands 1st becoming tubular, then filamentous (in pigs & ruminants). Up to 1 m long
in pigs. In horses, carnivores & primates the embryo stays spherical and doesn’t elongate.

Histotrophe: secretory product of endometrial glands (contains enzymes, growth factors, hormones). These glands undergo hypertrophy
during gestation for maximu m histotrophe production (in sheep, cows, goats, pig, horse and less so in primates). It nourishes embryo
during pre and post implantation depending on species.

Maternal Recognition & Maintenance of Pregnancy


 Animals detect presence/absence of embryo in repro tract.
 Luteolysis must be prevented – corpus luteum produces progesterone which maintains pregnancy & develops after dominant
follicle ovulates. CL supports secretory function of endometrium, embryonic development, implantation, and placentation.
 Rabbits/Cats are induced ovulators & have a luteal phase for duration of gestation regardless of embryo prese nce – NO signal
required from conceptus.
 Other spp – luteal phase ends before implantation, thus pregnancy-recognition signal needed from conceptus to prolong CL.
 Recognition Signalling:
o Luteotrophic – hormone that acts on CL to promote growth/maintenance of CL.
o Anti-luteolytic – hormone that prevents uterine release of luteolytic promoting substances such as prostaglandin F2-
alpha.
 Cat & Dog – none needed, Cow & Ewe – IFN-tau, Sow – estradiol, Mare – eCG & embryo migration, Human – hCG
o IFN-tau – acts on endometrial cells and inhibits oxytocin receptor production – therefore oxytocin cannot stimulate
PGF2-alpha synthesis. It increases endometrial gland secretions.
o Estradiol – reroutes PGF2-alpha to uterine lumen where it is destroyed preventing Luteolysis.
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o Migration – pre-attachment conceptus is moved over endometrial surface by uterine contractions ~12-14 times/day.
Conceptus produces & distributes pregnancy recognition factors that reduce PGF2-alpha production.

Implantation: movement, transient attachment, and firm adhesion of trophectoderm to uterine epithelium.
It has 5 phases:
1. ZP shedding
2. Pre-contact period – blastocysts migrate and undergo orientation without contact with epithelium – pregnancy
recognition signally initiated.
3. Trophectoderm associates with endometrial epithelium for unstable adhesion. In ruminants microvilli begin development.
4. Trophectoderm firmly adheres
5. Unique to species w/ invasive implantation – blastocyst invades uterine epithelium and moves into stroma.
It has 3 types:
1. Interstitial Implantation (A/B): blastocyst invades uterine epithelium and into stroma where embryo develops (primates,
guinea pig)
2. Eccentric Implantation (C): blastocyst lodges into uterine fold/cleft and uterine mucosa proliferates around it (rodents)
3. Centric Implantati on (D): fluid filled sac (amnion & chorion) around embryo tightly associate to uterine epithlium and
attach to it ( horses, cattle, sheep, pigs, dogs, cats, rabbits).

Diapause: delayed implantation – blastocyst enters a period of decreased cell division and metabolic quiescence and delayed
implantation. Has 2 types:
1. Seasonal Delayed: increases probability that offs pring are born during a favorable time of year that improves survival (roe
deer, bears, badgers, seals, marten).
2. Facultative/Lactational Delayed: can be pregnant during post -partum estrus while still feeding pups, implantation delayed until
weaning is complete to prevent the mother from having to support 2 litters at once (rodents, marsupials).

Marsupials – do not produce a pregnancy recognition signal, prematurely born fetus attaches to teat and stimulates a recognition signal
that induces diapause for any future embryos until weaning is completed.

Early Embryonic Development III

Twinning – 2 individuals develop during same pregnancy in animals that are monocotous.
1. Dizygotic – twins arising from 2 ova, produced from separate follicles, each fertilized by a single sperm.
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2. Monozygotic – twins arising from single ovum fertilized by single sperm
a. 2-cell stage pre-implantation embryo splits w/ each blastomere
going on to produce an embryo. ~30% of cases & can happen in
cattle.
b. Duplication of ICM. Twins develop w/ shared yolk sac and chorion
but separate amnions. ~ 70% of cases & can happen in sheep.
c. 2 primitive streaks form giving rise to 2 offspring. Share a common
amnion, yolk sac, and chorion. If streaks do not separate properly
can get conjoined twins.
Twinning common in humans (1 in 85) and cattle, sheep, and horses with about a 2-
5% incidence.
Consequences: high abortion rate, poor neonatal viability, growth retarded fetuses,
reduced fertility after twin abortions, dystocia.

How to deal w/ twin pregnancies in Horses:


 Before 40 days: manual trauma to fetus
 After 40 days: manual trauma, ultrasound guided puncture or injection, surgical removal.

Gastrulation
 a stage in the epiblast of cell proliferation, migration, and differentiation that results in the formation of the 3 germ layers:
ectoderm, mesoderm, and endoderm that can give rise to all tissues/organs of the embryo.

Ectoderm: epidermis of skin, epithelium of oral/nasal cavities, nervous system, sense organs
Mesoderm: muscle, connective tissue, bone, components of circulatory, urinary, and genital systems
Endoderm: mucosal epithelium and glands of respiratory and digestive systems.

 Formation of primitive streak along midline


 Epiblast thickens, and then ingression of epiblast cells into space b/w epiblast and hypoblast occurs starting at primitive node.
o Ingressing cells known as meso-endodermal cells & are mesenchymal.
 Some cells integrate w/ then displace the hypoblast becoming endoderm. ]
 Under the endoderm and hypoblast is the primitive yolk sac.
o The part of the yolk sac under the endoderm incorporates into primitive gut, while the rest will be extra -embryonic –
the definitive yolk sac lined by hypoblast.
 Mesenchyme that move cranially and laterally but stay b/w endoderm and epiblast will be intra-embryonic mesoderm.
 Cells migrating further laterally b/w hypoblast and trophectoderm will be extra-embryonic mesoderm.
o Extra-embryonic mesoderm splits into:
 Somatic (parietal) mesoderm associating w/ trophectoderm
 Visceral (splanchnic) mesoderm associating w/ hypoblast.
 Cavity b/w these layers is the extra-embryonic coelom.
 Embryo grows by cells moving cranially and embryonic disc becomes oval w/ primitive streak regressing caudally.
 A prominent midline structure is then formed by epiblast cells which have migrated through the primitive node – this is the
notochord – which is a column of mesoderm establishing a cranial-caudal axis & embryo has R/L halves.
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Neurulation
 Neural Fold  Neural Tube
 Neural Tube Morphogenesis
o Neural plate cells elongated on dorsal ectoderm
o Medial hinge point cells become attached to notochord by narrowing on 1 side.
o Apical cells of neural folds approach each other to form a tube by changing of shape
(wedges) of dorsolateral hinge point cells and expressing molecules (N-cadherins) to
adhere cells to one another.
 Occurs along neck region and closes like a zipper in both directions.

Anencephaly: when the anterior neural tube does not close. This often results in a baby being born without
the front part of the brain (forebrain) and the thinking and coordinating part of the brain (cerebrum). The
remaining parts of the brain are often not covered by bone or skin.

Spina Bifida: when the posterior neural tube does not close.

Neural Crest Cells – when neural folds are fusing to form the tube cells at the crest begin to detach. They
form many tissues – melanocytes, craniofacial mesenchyme derivatives (otic capsule, palate), pharyngeal
arch cartilages, dorsal root ganglia, parasympathetic ganglia, and enteric ganglia. They arise via Epithelial
Mesenchymal Transitions & aris from more than 1 germ layer.

Derivatives of Surface Ectoderm


 Otic Placode: invaginates into otic vesicle that developes into future ear.
 Lens Placode: invaginates into lens of inner ear.

Mesoderm:
 Notochord provides a midline axis which is a template for axial skeleton development.
 At first cells of mesoderm are loose mesenchyme on either side of notochord
 These become block-like (paraxial mesoderm)
 During neurulation in occipital region, mesoderm grows and forms pairs of somitomeres that will then form somites.

Somitogenesis: Each somite differentiates into 3 components  scleratome, dermatome and myotome (dermamyotome).
 Scleratome – patterns formation of vertebral column (vertebral bodies, intervertebral disks, ribs, and surrounding CT).
 Dermamyotome:
o Dermatome – forms the dermis & subcutaneous region of skin
o Myotome – forms muscles of back and limbs. It divides into epaxial and hypaxial myotomes.
 Signaling:
o Epaxial myotome – receives Wnt 1,3 signals from neural
tube, and low [Shh] from notochord
o Dermatome – receives Neurotrophin-3 signal from neural
tube
o Hypaxial myotome – receives Wnt from surface ectoderm
o Scleratome – receives high [Shh] from notochord

Endoderm:
 Inner epithelial lining of GI tract & lining of respiratory tract
 Body folding of endoderm portion of yolk sac forms primitive gut (foregut, midgu t, hindgut).
 Foregut  pharynx, middle ear, parathyroid glands, oesophagus, liver, stomach, pancreas & opens into amniotic cavity
 Midgut  small/large intestine, transverse colon
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 Hindgut  transvers and descending colon, rectum, anal canal (part).

Body Formation

 Evolution of extra-embryonic membranes or fetal membranes permitted reptiles, mammals, and birds to evolve on land.
 In early gastrulation, embryonic disc is covered by these membranes.
 Function to supply/store nutrients, gas exchange, waste excretion, mechanical & immune protection, hormone production.
 4 extra-embryonic membranes: chorion, amnion, yolk sac, allantois.

1. Yolk Sac
 First to form
 Mediates nutrition in birds/reptiles
 connected to midgut by yolk duct
 In primates – does not contain yolk but is the 1st hemopoietic organ in mammals and the source of PGCs.

2. Chorion
 Derived from the somatopleure (somatic mesoderm and trophectoderm).
 Outermost membrane – functions in gas exchange & respiration.
 Up against egg-shell in reptiles/birds.

3. Amnion
 Surrounds embryo proper & provides aquatic micro-environment which permits embryogenesis in water
 Prevents desiccation and acts as shock absorber.
 Amniotic cavity formed by fusion of somatopleure around the embryo.

4. Allantois
 Stores urinary wastes and mediates gas exchange
 Can become quite large in birds/reptiles and apposed to chorion keeping urinary wastes away from embryo
 In mammals the size depends on how well urinary wasters are removed by the chorionic placenta – can fill entire extra-
embryonic coelom.
 Anchor shaped in ruminants and pigs , tube shaped in horses, dogs, and cats.

Fetal Fluids – amniotic and allantoic fluids increase in volume during gestation. The fluid is like fetal and maternal blood plasma.
Secretions from skin and respiratory tract also goes into amniotic fluid while secretions from allantois go into allantoic fluid. Once
kidneys are functional urine also goes into the fluid.

Hydrops – excessive accumulation of fetal fluids in either amnion or allantois in cattle.


 Hydrallantois: ~6-9 months of gestation, with up to 40x excess fluid. Clinically presents as progressive distension of the right
abdominal wall and though to be a result of placental abnormalities.
 Hydramnion: in cows 8-10x normal fluid level associated w/ malformation of digestive system.

Lateral body folding gives rise to a L & R intra-embryonic coelom surrounding the developing gut.
 Lateral plate mesoderm splits creating clefts along side of embryo.
 These fuse into intra-embryonic coelomic cavities on R and L of embryo. The cavities extend cranially in front of neural plate.
 Following body folding, the cranial portion of the horseshoe shaped coelom will be ventral to the foregut and developing
heart.

Formation of Pericardial and Peritoneal Cavities

1. Developing heart/lungs surrounded by L/R segments of pleuro -pericardial cavity – Heart will eventually be suspended in one
pericardial cavity when ventral and dorsal mesocardium are lose.
2. Folds of mesoderm – pleuro-pericardial folds grow medially into the L and R parts of the cavity where they fuse to separate the
pleural from the pericardial cavity.

Formation of Diaphragm: separates pleuro-pericardial cavity from the peritoneal cavity.

Pleuro-peritoneal folds from lateral body wall fuse with the septum transversum and the mesoesophagus resulting in the formation of
the primordial diaphragm.
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Diaphragmatic Hernia – when components of primordial diaphragm do not fuse and completely partition the thoracic cavity
from the abdominal cavity. Congenital DH – when abdomi nal viscera pass through opening into thoracic cavity  two types:
pleuro-peritoneal herniation & peritoneal-pericardial herniation.

1. Pleuro-peritoneal Hernia: failure of one or both of pleuro-peritoneal folds to develop or fuse w/ mesoesophagus and
septum transversum. Usually on left side. Mostly in humans. Results in viscera such as stomach/intestines being present in
pleural cavity.

2. Peritoneal-pericardial Hernia: defect in development of septum transversum leading to improper communication b/w
peritoneal and pericardial cavities. Results in liver, pyloric region of stomach, and intestines into pericardial cavity.

Traumatic Diaphragmatic Hernia: not congenital, happens in HBC (hit by car) cases.

Peritoneal Cavity: lateral body folding results in a L/R intra-embryonic coelom surrounding the developing gut. The gut is suspended
by folds of splanchnic mesoderm b/w the coelomic cavities lined by mesothelium. Later, ventral mesentery caudal to duodenum and
cranial to the rectum atrophies – gut is then suspended only by a dorsal mesentery which allows it to grow in length and rotate – single
peritoneal cavity is now present.

Schistosomus Reflexus – affects ruminants, leads to dystocia, malformed calves that cannot pass through birth canal, fetus removed by
C-section (removes whole fetus) or fetotomy (chop it up, pull it out piece by piece). Fetus – head, limbs, tail all in close proximity
(ventral convex curvature & acute angulations of spinal column), limb fusion/stiffness (ankylosis), failure of the closure of all or part
of the ventral wall of the fetal body resulting in exteriorized viscera.

Gastroschisis – failure of ventral body wall to close in abdominal region leading to abdominal contents outside body cavity
through a fissure b/w umbilicus and sternum.

Congenital Umbilical Hernia – assoc. w/ abdominal ventral body wall defect, protrusion of viscera occurs around umbilicus due to lack
of muscular body wall, affects small animals, very common in pigs, and Holstein-Friesian cattle.

Musculoskeletal Development

Consists of – bones, cartilage, muscles, ligaments, tendons.


Functions – support body, motion, protection of vital organs, storage for calcium and phosphorus.

Bone Formation
 Somites  axial or vertebral skeleton
 Lateral plate mesoderm  limb skeleton
 Cranial neural crest  branchial arches, craniofacial bones and cartilage

Osteogenesis
 Scleratomal mesenchyme of somites  segmented axial column (vertebra, ribs, sternum).
 Lateral plate mesoderm mesenchyme  appendicular skeleton (limbs & girdles).
 Ectodermal neural crest mesenchyme  facial bones & skull
 Intramembranous Bone Formation: Mesenchyme  Bone
o Mesenchyme coalesces into a blastema & some cells become osteoblasts and secrete osteoid (ECM of collagen, and
proteoglycans that can bind calcium & calcify & then ossify).
o Osteoblasts surrounded by osteoid are called osteocytes  calcification occurs and bony spicules form that fuse with
adjacent spicules
o Compact layer of mesenchymal cells form periosteum – surrounding the bone
o When BMP 2,4,7 is high neural crest cells form chondrocytes, when BMP 2,4,7 is low neural crest cells differentiate
into pre osteoblasts.
o Pre-osteoblasts secrete osteopontin and RUNX2 and become chondrocyte-like osteoblasts (CLOs).
o The CLOs secrete IHH and differentiate into mature osteoblasts.
 Endochondral Bone Formation: Mesenchyme  Cartilage  Bone
o Cartilage model formed & bone collar develops in local perichondrium (via intramembranous bone formation).
o In middle of cartilage framework (diaphysis) chondrocytes degenerate and matrix calcifies and blood vessels
penetrate brining osteoblasts and chondroclasts to area forming a primary ossification centre.
o Secondary ossification centre develops at epiphysis
o Cartilage continues in 2 regions: articular cartilage and epiphyseal cartilage.
 Epiphyseal cartilage is where bone elongation occurs and it has 5 zones:
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1. Resting Zone – non-proliferative chondrocytes
2. Proliferative Zone – chondrocytes proliferate/divide and form stacked columns
3. Hypertrophic Zone – chondrocytes increase in size
4. Resorption Zone – dying chondrocytes and calcification of cartilage matrix
5. Ossification Zone - new bone tissue formed by osteoblasts.
o Mesenchyme progenitor can produce Sox9 – if it does it becomes a chondrocyte, if it doesn’t it becomes a
perichondrial cell. Paracrine Wnt and BMP cause chondrocytes to become hypertrophic. Hypertrophic chondrocyte
expresses RUNX2 which causes perichondrial cells to also secrete RunX2 and differentiate into osteoblasts.
Hypertrophic chondrocytes also produce VEGF which stimulates blood vessel development.

Axial Skeleton (Vertebral Column): notochord induces surrounding mesenchyme to secrete Epimorphin – a chemoattractant for
scleratomal cells to move around the neural tube and notochord, coalesce and differentiate into c artilage. The scleratome cells split into
two populations: a loosely packed cranial segment, and a tightly packed caudal segment. The caudal half of one scleratome joins with
cranial half of the next to form the body of vertebra. Enables motor neurons to g row lateral and innervate newly forming muscles.
Endochondral ossification occurs but from centres of vertebral body and arches. Ribs arise from segmental scleratome -derived
mesenchymal condensations beside thoracic vertebrae. Distal ends of ribs grow ventral towards midline and fuse with sternal bars. The
sternal bars divide to form sternal vertebrae then undergo endochondral ossification.

Appendicular Skeleton (Limbs): mesenchyme cells migrate from limb fields in lateral plate mesoderm and somites and form forelimb
buds at 1st thoracic vertebrae (due to Hox6c expression). Limb bud becomes visible as protrusion with an apical ectodermal ridge.
Signalling in AER causes gradients of retinoic acid (high concentrations proximally) and FGFs (high concent rations distally) to form –
which stimulate regional expression of Hox genes and the patterning of limbs.
o Stylopod – Hox 9/10 – humerus and femur
o Zeugopod – Hox 11 – radius/ulna or tibia/fibula
o Autopod – Hox 13 – carpals and tarsals
Zone of Polarizing Activity – forms due to a Shh gradient - high [Shh] makes the thumb, low [Shh] makes the pinky form.
Digit Formation – BMP 2,4,7 expression results in interdigital tissue apoptosis . Noggin expressed in digit cartilage and represses BMP
expression so digits remain.

Skeletal Muscle Formation


 Dermatome  dermis of skin
 Myotome  myoblast cells  epaxials (intercostals, deep muscles of back) & hypaxials (body wall, limbs, tongue).

Myogenesis
 Neural tube and notochord secrete paracrine factors that cause myotome cells to secrete Wnt, Shh, MyoD and Myf5.
Dividing myoblasts secrete FGFs and align. Aligned myoblasts produce myogenin which allows myoblasts fuse to form
myotube which matures and forms a muscle fiber that can contract.

Cardiac and Smooth Muscle Formation


 Gut and respiratory tract cardiac/smooth muscle arise from splanchnic mesoderm which was originally lateral plate mesoderm
 Some smooth muscle cells originate from local mesoderm.

Tendon Formation
 Myotome secretes FGF8 which induces mesenchyme cells to become syndetome which gives rise to tendon forming cells.
 Syndetome cells migrate along vertebrae or developing ribs to other sites and form tendons.

Cardiac and Smooth Muscle – arise from splanchnic mesoderm (lateral plate mesoderm originally).

Respiratory System

 Respiratory primordium develops as ventral groove in foregut floor at level of 4 th pharyngeal arch.
 Groove deepens and forms elongated outgrowth.
 Groove separates from foregut by two trachea-oesophageal grooves that approach each other and fuse to form trachea-
oesophageal septum which separates foregut from laryngo-tracheal tube.
 Portion of foregut cranial to trachea-oesophageal septum will be the pharynx, and caudal to it the oesophagus.

Larynx
 Cranial portion of laryngo-tracheal tube becomes larynx with stratified squamous epithelium (derived from foregut
endoderm), caudal part gives rise to trachea & bronchial tree.
 Cartilage and muscle are neural crest origin.
 Neural crest mesenchyme from pharyngeal arch forms swellings lateral to laryngo -tracheal groove.
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 Swellings make cranial end of groove into T shaped opening.
 Swellings become epiglottic and arytenoid cartilages
 Larynx initially has epithelial blockage of lumen until cartilage/muscles develop and can regulate lumen diameter – blockage
lost later in development.
 As cartilages develop vocal folds are formed and laryngeal ventricles – which constrict to regulate lumen.
o Ventricles start as L/R diverticula in larynx walls – present in horses, dogs, pigs.

Trachea
 Caudal part of laryngotracheal tube splits into 2 bronchial buds.
 Primitive trachea: endoderm lining that becomes ciliated, pseudo -stratified epithelium rich in goblet cells; neural crest
mesenchyme that forms cartilaginous rings and smooth muscle.

Pleural Cavities: pleuro-pericardial folds grow medial into L and R parts of pleuro-pericardial cavity and fuse to separate pleural from
pericardial cavity. Heart eventually loses ventral and dorsal mesocardium and is suspended in 1 pericardial cavity.

Bronchi & Lungs


 Embryonic – primordium of lungs/bronchi formed
o Lung buds fork & grow caudo-laterally to form principal bronchi  lobar bronchi that push into pleural cavity and
surround with mesenchyme that forms pleura  segmental bronchi
 Fetal – bronchi branch and form preliminary structures for exchange.
o Pseudoglandular: segmental bronchi  terminal bronchioles
o Canalicular: terminal bronchioles  respiratory bronchioles  canalicules
o Saccular: Canalicules  terminal saccules  blind saccules
o Alveolar: blind saccules  alveoli (distally 1st ) w/ epithelium that becomes squamous Type I and cuboidal II alveolar
cells.
 Postnatal – extensive growth, alveoli form and take on adult form.
o Primitive alveoli allow new born to breath
o Mature alveoli form after birth
o Lung fluid is expelled or absorbed by epithelial cells

Signalling:
 Mesenchyme produces FGF10 which causes lung buds epithelium growth towards mesenchyme
 BMP-4 secreted from apical epithelial cells initiates branching – Shh and TGF-beta inhibit FGF10 and induce
fibronectin/collagen to form at the tip of the branch so growing stops in the middle but laterally the bud keeps growing
forming branches.

Clinical Relevance: Ectopic lung tissue found in abdominal cavity


Cyst formation in lungs – causes dilated terminal bronchi that fill w/ glandular fluid, results in respiratory distress or chronic
pulmonary infections – can be surgically removed.

Cardiovascular I

 Heart arises from splanchnic or visceral mesoderm


 Progenitor cells in two small patches on both sides of epiblast enter primitive streak and move towards outer edge forming
lateral plate mesoderm.
 Endoderm of pharyngeal region that progenitors migrate on helps regulate heart development by secreting BMP2 which
induces NKx2-5 and Mesp1
 Progenitor cells migrate anterior and form cardiogenic field which is separated into two regions – 1st region is scaffold of heart
tube and eventually L-ventricle, 2nd region adds conus cordis & truncus arteriosis & R-ventricle, and inflow region of
pulmonary vein and vena cava. Neural crest cells form septa that separate aorta from pulmonary tract.

Primitive Heart Formation ~ day 23


 Folding places heart into pericardial cavity ventral to embryonic disc.
 Cardiogenic is bent with embryonic folding – anterior part of horseshoe bent ventrally to become ventral aorta, posterior part
of horseshoe becomes dorsal aorta.
 Posterior part of the extension fuses with venous system
 Cardiac tube then grows differentially into a segmented tube forming: sinus ven osus (posteriorally), atrium, ventricle, bulbis
cordis, and truncus arteriosus (anteriorly) that can pump blood
 Sinus venosus (early pacemaker) and atrium not enclose by pericardial cavity at first but with growth and bending become
enveloped in it.
Samantha Bray 12
 Heart tube growth outgrows pericardial cavity which causes the heart to bend contributing to final conformation.

Development of Chambers
 Atrioventricular canal:
o Mesenchymal endocardial cushions b/w endocardium and myocardium move towards each other and fuse forming
the septum intermedium resulting in L and R atrio-ventricular openings

Division of Atriums
 Septum primum arises from dorsal wall of atrium and moves towards endocardial cushions – forms L & R atria
 Apoptosis creates foramen secundum. Septum secundum develops from dorsal wall of R atrium and grows towards septum
intermedium (endocardial cushions)
 Opening remains b/w free edge of septum secundum and foramen secundum called foramen ovale.
 Upper part of septum primum fuses w/ septum secundum and rest becomes a valve -like structure for the foramen ovale.
 Septum secundum fuses w/ intermedium dividing blood flow returning to heart from caudal vena cava into two streams. Most
goes through foramen ovale into L atrium, less goes into R atrium. At birth foramen ovale closes forming completely separate
atria.

Arteries of the Atria


 Sinus venosus has vitelline veins, umbilical veins and cardinal veins opening into it – forming a sinus horn. Right sinus horn is
favoured and incorporates with right atrium. Anterior part of R-sinus horn becomes cranial vena cava and posterior part
becomes caudal vena cava. L-sinus horn becomes coronary sinus
 Pulmonary veins start to open at L atrium – at 1st one opening draining 4 veins, but eventually 4 openings draining 4 veins .
 Original L-atrium becomes the L-auricle, and smooth walled atrium is from the incorporated pulmonary veins. Smooth walled
R-atrium from sinus venosus, original R-atrium becomes R-auricle.

Division of Ventricles
 Bulbus cordis has dilated part next to ventricle and non -dilated part called conus cordis which is continuous w/ truncus
arteriosus
 Intraventricular septum lengthens and fuses with septum intermedium dividing the ventricle into R and L halves.
 Wall of ventricle and bulbus cordis thickens then cavitation occurs

Division of Conus cordis and Truncus arteriosus


 Bulbar ridges develop and fuse together – at spiral orientations along length of tube – to form a aorticopulmonary septum.
 Results in separate outlets from R and L ventricles  conus cordis becomes the aorta emerging from L ventricle, and truncus
arteriosus becomes the pulmonary trunk emerging from R-ventricle.

Atrioventricular Valve Formation


 Mesenchymal edges of R/L atrioventricular openings grow out and thicken & cavitation occurs in ve ntricular walls
 L side – Bicuspid (mitral) valve; R side – tricuspid valve
 Muscular cords attached to valves replaced with connective tissue chordae tendinae & rest of muscle becomes papillary
muscles.

Semilunar Valve Formation


 Swellings of subendothelial mesenchyme (neural crest origin) that become hollowed out into 3 valves – in each of the aortic
and pulmonary outlets. Final formation prevents backflow of blood from vessels into ventricles.

Development of Conducting System


 In early heart tube myocardial cells initiated/conducted electrical signals.
 1st pacemaker = sinus venosus when incorporated into R atrium  future SA node
 As chambers develop atrio-ventricular bundle of Purkinje fibers form – conduct impulses from the AV-node in the septum
intermedium of the atria to ventricles.

Clinical Relevance

Teratology of Fallot: malformation of aortico-pulmonary septum and/or interventricular septum caused by mutation in NKx25 gene.
Causes pulmonary stenosis, enlarged aorta, right ventricular hypertrophy. Deoxygenated blood enters aorta from R ventricle and
hypertrophy caused by compensation for pulmonary stenosis.
Samantha Bray 13
Ectopic Cordis – in thoracic region when opposing sides of ventral body wall fail to fuse together (defective lateral body folding – heart
not enclosed in pericardium) – heart can be present outside the thoracic cavity – common in cattle (Lucky) – and can be found in neck
region.

Cardiovascular II

Embryo establishes blood vessels in yolk sac and allantois – allows respiration in chorioallantoic and choriovitelline membranes –
process called extraembryonic vasculogenesis.

Blood vessel formation requires 2 processes; vasculogensis and angiogenesis


 Vasculogenesis: initial bv formation from lateral plate mesoderm
 Angiogenesi: sprouting of bv from existing ones and remodelling of vascular beds

Cells posterior to cardiogenic field become hemangioblasts – within splanchnic mesoderm. These are precursors for blood cells and
blood vessels in yolk sac & only contribute to vessels in the embryo. Yolk sac endoderm secretes indian hedgehog signalling
sphlancic mesoderm form into blood islands

Extra-embryonic vasculogenesis

Inner cells of blood island become blood progenitor cells (rbcs, etc).
Outer cells become angioblasts that form blood vessels by differentiating into endothelial cells.

Vasculogenesis in yolk sac produces vitelline and umbilical vessels that bring nutrients to embryo, gas transport, and brings
blood cells from yolk sac to heart for distribution.
 Lumen Formation:
o Cells line up and form vacuoles that fuse to make a lumen, then cells fus e their lumens together to make a
continuous one.
o Cells form circle, form vacuoles that fuse to the intracellular lumens to form a lumen.

Intra-embryonic vasculogenesis

Vascular networks arise from angioblasts originating in mesodermal tissue in body.


Developing organs make paracrine factors that induce bvs to form in their mesenchyme.
Allows developing vessels of capillary networks to have own special properties for that organ.

3 growth factors needed: VEGF, PDGF,


Angiopoietins.

Vasculogenesis: angioblasts form blood


island and express VEGFR2 on surface,
VEGF secretion from mesenchyme
induces angioblast differentiation and their
proliferation into endothelial tubes.
Angiogenesis: occurs during VEGF
signalling – angiopoietin 1 in secreted by
mesenchyme and binds to Tie-2 receptor
now expressed on endothelial cells to
initiate sprouting.
Vascular Wall formation: mesenchyme
then secretes PDGF which recruits
mesenchyme cells, and endothelial cells
recruit smooth muscle & pericytes .
 Trunk & Extremities – wall from local mesoderm
 Head & Aortic Arch System – wall from mesenchyme from neural crest ectoderm – contributes to CT and smooth muscle.

Arterial vs Venous System

 Both originate from angioblasts


 Angioblasts that undergo lots of Notch stimulation express Ephrin B2 and become arterial endothelial cells.
 Angioblasts that undergo less Notch stimulation express Ephrin B4 and become venous endothelial cells that are thing and
form valves.
Samantha Bray 14
 Both arterial B2 and venous B4 endothelial cells are present in a vascular plexus and are important for anastomoses , and is
also important so that the same kind of endothelial cell is recruited when elongating a bv.

Arterial System
 Body folding places heart into a pericardial cavity and bends the developing aortae.
 Anterior extension of horseshoe = ventral aortae
 Posterior extension of horseshoe = joins w/ developing venous system
 Dorsal part of horseshoe becomes dorsal aortae.

Aortic Arches
 Forms from mesoderm within pharyngeal arches.
 Forms link b/w aortic sac and paired dorsal aortae
 Form lateral to the foregut and develop sequentially.

Derivatives of Aortic Arches


Aortic R side L side
Arch
1 Most disappears SAME
Part of maxillary artery
2 Most disappears Hyoid/Stapedial
Hyoid/Stapedial Arteries Arteries
3 Ventrally – Common SAME
Carotid artery
Dorsally – Internal
Carotid artery
4 Prox. part of R-subclavian Part of aortic arch
artery
5 Rudimentary (horse/pig) SAME
Never develops (cattle)
6 Part of R-pulmonary Part of L-pulmonary
artery artery
Ductus arteriosus
Derivatives from Aorta
 Paired dorsal aorta extend caudally until they fuse into
one vessel
 It gives rise to dorsal, lateral, and ventral segmental
arteries.
o Dorsal Segmental: paired, in each segment from
cranial somites to sacral region.
 Dorsal/spinal branches that supply neural tube.
 Ventral branches that supply ventral body wall (intercostal arteries and lumbar arteries).
 In cervical region, 7 pairs of dorsal segmental arteries disconnect from aorta and unit with seventh that
remains connected forming paired vertebral arteries which extends cranially and fuss forming a single
basilary artery (supplies brainstem).
o Lateral Segmental: develop in the unpaired part of the dorsal aorta and supplies organs developing from intermediate
mesoderm (urogenital organs).
 Mesonephric, adrenal, and genital ridge arteries become ovarian, testicular, and adrenal arteries in adult.
 Renal arteries develop with metanephros development.
o Ventral Segmental: supply yolk sac and allantois.
 Cranially: Vitelline arteries arise from unpaired part of aorta and supply the yolk sac.
 When yolk sac is lost the L-vitelline artery disappears, R one becomes coeliac artery and cranial
mesenteric artery.
 Caudally: Umbilical arteries arise from unpaired part of aorta and supply the allantois and placenta. Arteries
extend from aorta to the allantois through the allantoic duct in the umbilicus.

Clinical Relevance
 6 wk old – regurgitation undigested food, coughing, underweight. Xray showed a letward trachea deviation. Barium
esophogram showed a dilated and narrow portion of esophagus. Was formed by ligamentum areriosum (a complete vascular
Samantha Bray 15
ring around the esophagus and/or trachea). Happens when aortic arch develops from R-4 th-aortic arch artery, ductus
arteriosus develops as normal from the L-6 th-aortic arch and L part of dorsal aorta persists.

Cardiovascular III

Venous System
Vitelline v., umbilical v. and common cardinal v. empty into sinus venosus.

Vitelline Veins: bring blood from yolk sac to the heart


 pass through umbilicus running on either side of the gut, go through the septum transversum and enters sinus venosus.
 Cells of developing liver cords extend into septum transversum, and a venous plexus arises from vitelline veins forming the
hepatic sinusoids.
 L-cranial vitelline vein atrophies
 R-cranial vitelline vein becomes part of caudal vena cava.
 Two anastomoses form b/w caudal parts of L and R vitelline veins and forms the portal vein when the stomach rotates.

Umbilical Veins: bring blood from allantois (placenta) and pass through umbilical cord, septum transversum and into sinus ven osus.
 Altered w/ liver growth
 Middle part incorporated into tissue and forms hepatic sinusoids
 Cranial part atrophies
 Caudal part of:
o R-umbilical v. atrophies
o L-umbilical v. enlarges and moves oxygenated blood from placenta to embryonic liver. Develops into a venous shunt
with cranial part of R-vitelline vein forming ductus venosus. The dv persists up to birth in carnivores, ruminants and
atrophies in gestation in horses and pigs.

Cardinal Veins: paired, cranial cardinal v. drain head and neck, caudal cardinal v. drain body wall. Cranial and cau dal cardinal v. on L
and R side fuse and form common cardinal v. that empties into sinus venosus.
 Cranial cardinal v.  internal and external jugular veins, brachiocephalic veins, cranial vena cava.
 Caudal cardinal v.  subcardinal v (drain mesonephros), supracardinal v. (drain dorsal body wall).

Caudal vena cava formed by parts of R-vitelline v. caudal


cardinal v. and supracardinal v.

Lymphatic System:
drains fluid and transports lymphocytes.

 Produced by Prox1 transcription factor and starts


differentiations from venous bv.
 Forms 6 primary lymph sacs : 2 jugular sacs, 1
retroperitoneal sac, cisterna chyli, iliac sacs.
o Jugular sacs drain head, neck, forelimbs. Originally connected to cisterna chyli by lymph vessel, following
anastomosis and reorganization to form thoracic duct.
o Retroperitoneal & cisterna chyli drain viscera
o Iliac sacs drain pelvic region, hindlimbs.
 Late into development the sacs are all interconnected by lymph vessels and drainag e system is fully established.

Lymphnodes
 All lymphsacs except cisterna chyli convert into lymphnodes by accumulating lymphoid tissue and mesenchyme cells
(mesoderm origin) infiltrate to form channels.
 Later in development more nodes develop along lymph vessels throughout whole body.
 Typical mammals – lymph nodules are found in cortex region of lymphnode.
 Pig – lymph nodules found in medulla region of lymphnode.

Circulation Before and After Birth

Before
 Oxygenated blood travels from placenta in L-umbilical v. to liver where most bypasses sinusoids via/ ductus venosus entering
into caudal vena cava.
Samantha Bray 16
o The blood that doesn’t bypass the sinusoids mixes w/ deoxygenated blood from portal v/ and also enters the c audal
vena cava.
 The oxygenation of blood entering the R- atrium of the heart is reduced relative to the blood that originally came from the L-
umbilical v.
o Blood goes into R-atrium, hits septum secundum and is directed into foramen ovale and into L-atrium where it mixes
w/ blood that has a lower pO2 and leaves the LA via aortic arch.
 Coronary a. and brachiocephalic trunk are first branches of aorta and thus have most oxygenated blood that goes to heart and
brain.
 Some blood from caudal vena cava enters the R-atrium and moves into R-ventricle where it mixes w/ deoxygenated blood
returning from head via cranial vena cava.
 Blood pumped to pulmonary trunk but there is great flow resistance b/c of non -functioning lungs. Blood is then directed
through ductus arteriosus to caudal aorta and returns to placenta through umbilical a.

After
 Just before birth, Umbilical a. contract to prevent passage of blood to placenta.
 At birth, Umbilical v. contract and forces blood in placenta into newborn circulation.
 Ductus venosus in liver contracts and stops blood flow through shunt.
 Right after, ductus arteriosus contracts and closes shunt
 Foramen ovale closes
 Umbilical a. remnants form round ligaments of bladder
 L-umbilical v. becomes round ligament of liver.

Figure 2. Circulation after birth


Figure 1. Circulation before birth

Clinical Relevance

Patent Ductus Arteriosus (PDA)


 Leads to rising pressure in aorta and L-ventricle forcing blood from aorta into pulmonary artery and sometimes into right
ventricle
 Cardiac output increases in response to maintain circulation for normal function
 Presents as machine-like or continuous murmur on auscultation over region of aortic and pulmonary valves.

Digestive System

Digestive tract has 3 parts; foregut, midgut, hindgut – midgut is continuous with yolk sac.

Foregut – pharynx to upper duodenum & accessory digestive glands


Midgut – lower duodenum to cranial half of transverse colon
Samantha Bray 17
Hindgut – caudal half of transverse colon to anal canal.

Blind end of foregut is apposed to ectodermal indentation in head region – called stomodeum which becomes the oral cavity.
Ectodermal depression is in contact with endodermal end of hindgut – called proctodaeum.
- Forms oropharyngeal membrane and anal/cloacal membrane

Lateral body wall folding causes the gut to be suspended dorsally and ventrally by double mesothelium – called dorsal and ventral
mesenteries (exception is esophagus and anal canal).
 Ventral mesentery atrophies caudal to small intestine and cranial to terminal part of hindgut. Alimentary Tract –
 Vascular, lymphatic and nerve supply is in b/w the folds of dorsal mesentery. esophagus to anus
 Molecular interactions b/w endoderm and mesoderm are needed for normal alimentary tract
development. Sonic hedgehog expressed in endoderm of gut influences mesoderm and induces BMP-4 in splanchnic
mesoderm which leads to smoth muscle development in the tract from the mesoderm.
o Epithelium and glands of GIT arise from endoderm (mucosa and submucosa)
o Smooth muscle and CT arise from splanchnic mesoderm (muscularis externa and serosa)

Carnivores have short, small volume tracts


Herbivores have long, large volume, compartmentalized tracts.

Esophagus – extends from tracheal groove to the primordial stomach. Endoderm is surrounded by somatic mesoderm of head – this
develops into skeletal muscle (although there is some spp. variation). Epithelium starts out columnar but becomes stratified squamous
in all spp (and is keratinized in ruminants).
 Ruminants – entirely skeletal muscle
 Carnivores – smooth muscle at terminal portion then mostly striated.
 Porcine – mostly striated, short portion near stomach is smooth m.
 Horses – last 1/3 is smooth m.

Stomach – fusiform expansion of caudal foregut – attached to dorsal and ventral abdominal walls by dorsal and ventral mesogastria.
Dorsal part of stomach grows faster than ventral – forms a greater curvature and a lesser curvature. Faster growth at cranial end forms
fundic region of stomach.
 Undergoes 2 partial rotations: 90 degrees to L about cranial/caudal axis and 45 degrees in anti-clockwise direction about
dorsal/ventral axis.
 Carnivores, Horses, Pigs: simple stomach w/ single compartment and has a cardia, fundus, body, and pyloric region.
 Ruminants – 4 chambered stomach – rumen, reticulum, omasum, abomasum.

Ruminant Stomach
 30 days – stomach is simple (like monogastrics), the fundic region extends and becomes primordia of rumen and reticulum.
Lesser curvature evaginates and forms the embryonic omasum and caudally forms an abomasum.
 Rumino-reticulum undergoes greater growth and is separated by a rumino -reticular groove.
 Rumen continues growth and divides into a dorsal and ventral sac.
 Rumen rotates ~150 degrees dorsally and caudally and displaces the rest of the stuff in the abdomen to the R-side.
 At birth, abomasum capacity is 2x size of other compartments combined
 Lining of rumen, reticulum and omasum becomes stratified squamous epith. While columnar absorptive cells remain in
abomasum (which eventually becomes the glandular stomach).

Liver – begins development as a ventral sac that comes from caudal foregut.
 It grows cranio-ventral into ventral mesogastrium and even into septum transversum. Ventral mesogastrium around
endodermal lined hepatic sac induces liver development via FGF-1,2,8.
 Septum transversum mesoderm produces BMP 2,4,7 which drives foregut endoderm to become hepatic epithelium.
 Hepatic endoderm epith. grow and form plates. Further development of these cells is induced by Hepatic growth factor (HGF)
which is secreted by mesoderm of septum transversum.
 CT of liver arises from mesenchyme of septum transversum and splanchnic mesoderm forming the capsule and peritoneal
coverings.
 Caudal part of liver forms gallbladder and cystic duct.
 Cranial part of liver attaches to diaphragm by coronary ligament and laterally to body wall by lateral ligaments.
 Lesser omentum forms from mesoderm of septum transversum and ventral mesogastrium.
 Mesoderm b/w liver and ventral abdominal wall forms falciform ligament.

Pancreas
Samantha Bray 18
 Dorsal and ventral endodermal outgrowths from caudal foregut due to expression of Pdx1 (pancreatic and duodenal
homeobox-1) in endoderm.
o Dorsal bud develops b/w layers of dorsal mesogastrium
o Ventral bud develops from liver sac near its origin and within ventral mesogastrium.
 Buds grow in tree like fashion and produce ducts w/ secretory acini.
 Stomach and intestinal rotations cause the ventral and dorsal pancreatic buds to overlap and fuse – producing a single
structure with a body and left (originally dorsal) and right (originally ventral) lobes.
 Duct of ventral lobe or pancreatic duct joins with bile duct and forms common bile duct opening into duodenum. Duct of
dorsal lobe will become the accessory pancreatic duct.

Intestine
 Midgut and hindgut lack a ventral mesentery – allows midgut to elongate (midgut loop).
o Descending limb of loop forms duodenum, jejunum, and part of ileum.
o Ascending limb forms part of ileum, caecum, ascending colon, and prox. part of transverse colon
 Loop increases in size and moves into part of extra-embryonic coelom (umbilical sac) – a physiological umbilical herniation.
 Loop also rotates 180 degrees
 Descending limb increases in length and produces many coiled loops within umbilical sac.
 Ascending limb grows slow and develops into cecum.
 As midgut lengthens it returns into abdominal cavity which has enlarged.
 Positions of gut structures are similar in domestic spp. the length and position of ascending colon differs b/w spp.

Ascending Colon – spp differences

Ruminants
 Cecal diverticulum increase in size, ascending colon lengthens and forms loop (suspended by dorsal mesocolon). Loop coils
as it lengthens. Material in coils travels centripetally then centrifugally.
 Coils arranged conically and then circular in a single plane (around 2-4 months of gestation).
 Displaced to the side by rumen.

Porcine
 Similar to ruminants – but coils stay in cone shape.
 Outer longitudinal muscle layer arranges in bands or taeniae.
 Structural changes occur in 2nd month of gestation.

Equine
 Site of cellulose digestion
 Extra large cecum and ascending colon
 Large colon elongates but does not coil – consists of 4 segments and 3 flexures

Cloaca
 Becomes divided by urorectal septum into an anorectal canal dorsally and urogenital sinus ventrally.
 Urorectal septum fuses with cloacal membrane dividing it into two membranes; anal membrane and urogenital membrane
 Urorectal septum gives ruse to fibromuscular mass called perineal b ody.

Clinical Relevance

Imperforate Anus: result of failure of anal membrane to break down during development – usually associated with atresia of the
rectum. Clinically apparent at birth – associated with abdominal pain and distension, retention of feces. Surgically repaired by
removing membrane. Common in cattle and pigs.

Omphalocoele: an embryonic hernia that occurs in umbilicus. Occurs when intestinal loops fail to return to abdominal cavity from
umbilical sac – they push through enlarged umbilical ring covered by amniotic epithelium. May be a genetic etiology and can be
corrected surgically.

Urinary System I

 Paraxial mesoderm becomes somites.


 Between somites and lateral plate mesoderm is intermediate mesoderm.
 Intermediate mesoderm  urinary and reproductive systems
 Paraxial mesoderm induces intermediate mesoderm to form kidneys
Samantha Bray 19
o Requires expression of Lim1, Pax 2, and Pax 8 in intermediate mesoderm which drives nephric tubule development.

Holonephros: pronephros, mesonephros, metanephros.

Pronephros – somite stage of development


 Intermediate mesoderm cells in cervical region form inner visceral and outer parietal layer with a nephrocele cavity b/w.
 Nephrotomes (cords of cells) grow from parietal wall and form pronephric tubules.
 Distal end of pronephric tubules grow out laterally and then moves caudally to fuse with the tubule right behind it forming a
pronephric duct.
 Pronephric duct grows towards the cloaca and becomes canalised.
Pronephric tubule is continuous w/
 Glomeruli form as tufts of capillaries that branch from the dorsal aorta into
nephrocele which opens into coelom
the pronephros (angiogenesis).
via nephrostome
 Tuft invaginates into wall of pronephric tubule and forms an internal
glomeruli in higher vertebrates.
 Invaginated epithelium around each glomerulus becomes a Bowman’s Capsule.
 Function: an internal glomerular filtration produces a filtrate that moves to the pronephric tubule. Water and electrolytes a re
re-absorbed and waste products move to pronephric duct then cloaca.

Mesonephros – post-somite stage of development


 Urogenital ridge develops as a proliferation of intermediate mesoderm in the thoraco-lumbar region and projects into
peritoneal (abdominal) cavity.
 Pronephric duct induces mesonephric tissue to form nephric vesicle then mesonephric tubule.
 Glomerular tufts from dorsal aorta invaginates into mesonephric tubule and form Bowman’s capsule of Renal Corpuscle.
 A peri-tubular capillary network develops around each mesonephric tubule – aids in reabsorption of water/electrolytes.
 Mesonephros – has multiple tubules at each somite. Whereas, pronephros has a single tubule at each somite.
 Mesonephros is large in pigs, and is less prominent in horses, ruminants and carnivores, and is poorly developed in primates
and rodents.

Metanephros
 Formed by ureteric bud (outgrowth from mesonephric duct) and metanephric mass (region of urinary ridge) in the sacral
region.
 Ureteric buds extend cranially into metanephric mass then widens.
 Widened portion gives rise to pelvis of kidney and undergoes branching to produce collecting ducts of kidneys.
 Collecting ducts induce metanephric tissue to form metanephric tubules.
 Metanephric mass is essential for ureteric bud formation, and ureteric bud is Ureteric bud branching influences
essential for survival of metanephric mass. final kidney arrangement (unilobar,
multilobar).
 Retanoic Acid and GDNF in metanephric mass induces branching of ureteric
bud.
 Branching induces Wnt 6 and Wnt 9b expression which induces mesenchyme to become tubular and epithelial cells form.
 Epithelial cells secrete Wnt 4 which allows the development of the rest of the nephron.
 Podocytes develop from epithelial cells and secretes VEGF which induces vasculogenesis and then angiogenesis which drives
capillary tufting from renal artery giving rise to the glomerulus.

Urinary System II

 During differentiation, metanephros moves from pelvic to dorsal lumbar region.


 Left is last and lagging (except in pigs)

Kidney Organization
 Outer Cortex: renal corpuscles, PCT, DCT.
 Inner Medulla: LOH, collecting ducts.
o Medullary Pyramid – made by conical arrangement of LOH and collecting ducts – base of pyramid covered by
cortex, and apex is a papilla that projects into pelvis of kidney.
o Renal Lobe – medullary pyramid with cortex covering.
 Unilobar or Multilobar based on species.

Partitioning of Cloaca
 Urorectal septum (mesoderm) is found b/w the hindgut and base of allantois.
 Septum grows towards cloacal membrane and divides cloaca into rectum and urogenital sinus with their own anal and
urogenital membranes.
Samantha Bray 20
Bladder
 Develops from pelvic region of urogenital sinus (after cloacal partitioning), while caudal part forms the urethra.
 Urogenital sinus is continuous with allantois.
 Distal end of allantois forms urachus
 Bladder grows and incorporates the terminal parts of mesonephric and ureteric ducts.
 Each duct develops separate openings into the bladder – with mesonephric ducts initially anterior to the ureteric buds.
 Gradually positions shift so ureteric buds finally open into bladder laterally and anterior to mesonephric ducts
 Trigone region – in dorsal wall of bladder – where the mesonephric and ureteric buds are incorporated.

Clinical Relevance

Renal Agenesis – complete absence of one or both kidneys – can be assoc. with absence or ureter. Unilateral form common in pigs and
dogs (beagles) due to familial predisposition. Results from failure of development of one or both ureteric buds – metanephric mass
NOT induced to form renal tubules (NO Wnt 6 and Wnt 9b signalling).

Renal Hypoplasia – small kidneys due to immature glomeruli and tubules. Exists in unilateral and bilateral forms. Common in dogs.
Treatment is managing chronic renal failure. Not enough signalling occurs for proper ureteric bud development. Unilateral usually
asymptomatic, bilateral assoc. with death.

Migration Defects – leaves a kidney in pelvic cavity. Cross ectopia – when one kidney and its ureter are on the same side as other
kidney. Usually asymptomatic but is assoc. with increased infections.

Horseshoe Kidney – fusion of kidneys at inferior pole. Asymptomatic but may be painful and ureters may be obstructed. Results from
metanephros not separating ureteric buds OR the kidneys fuse.

Polycystic Kidney – multiple cysts form in kidney causing it to enlarge. Result of failure of developing nephrons to connect with their
collecting ducts. Cysts arise from urine accumulation within nephrons. Common in beagles, bull terriers, and west hig hland white
terriers, hereditary in pigs, and is common in Persian and long haired cats. Is an autosomal dominant trait.

Ectopic Ureter – ureters attach to the urethra (or vagina in females). Results in urine leakage (b/c urethra and vagina are low in
muscular tone). Common in horses, 3-6 month old dogs and females at higher risk. Results from improper development of the
metanephric duct system. Can be surgically repaired.

Urachal Remnant – results from incomplete urachal closure (patent urachus ). Seen in all domestic species (esp. cats, dogs, horses). Is
associated with urine leakage, urine scalding of ventral abdomen, and bacterial UTIs. Can be surgically corrected.

Genital System I

Sex Determination: determined genetically – XX vs XY

Male Gonad Development - XY

PGCs
 Epiblast cells are put aside in the yolk sac and allantois and become PGCs (during formation of embryonic layers).
 Mammals: PGCs move via active chemotaxis toward the gonadal ridge.
 Birds: PGCs move via circulatory system.
 Teratomata: forms when PGCs migrate to wrong area and don’t die by apoptosis.

Gonadal Ridge
 Forms from intermediate mesoderm medial to kidneys. AKA bipotential gonad because it can form either ovaries or testis.
 PGCs multiply until meiosis (female) and arrest (males). PGCs are enclosed in the gonadal ridge during the 1st 15% of
gestation. AKA then bipotential gonad because it can form either ovaries or testis. Lies medial to kidneys.
 PGC arrival at gonadal ridge causes ridge elongation.
 Cells originate from:
o Intermediate mesoderm mesenchyme
o Coelomic epithelium
o Cells from mesonephric tubules  forms primitive sex cords that incorporate PGCs
 WT-1 gene needed for gonad formation
 Lim 1 needed for gonad formation (absence = no gonads)
 Steroidogenesis Factor-1 induces differentiation of Sertoli and Leydig cells
Samantha Bray 21

 Paramesonephric ducts (mullerian) develop as mesonephros is developing.


 Gonad and paramesonephric duct, remnant mesonephros and mesonephric duct start regressing caudally while the
metanephros develops and migrates cranially.
o Mesonephros – future efferent ducts
o Mesonephric duct – future epididymis
o Paramesonephric duct – atrophies

SRY gene
 Sex chromosomes in sperm determine sex of embryo.
 The Y chromosome contains a SRY gene that encodes SRY protein.
 SRY protein is made by sex cords and stimulates male gonad development.

Development of Testes
 Sex cords align with rete tubules
 5-15 mesonephric tubules penetrate the gonad then later interconnect with the sex cords.
 Sex cords become epithelial (has some Sertoli cells)
 Paramesonephric duct atrophies due to AMH produced by Sertoli cells

Development of Seminiferous Cords


 Sex cords proliferate into seminiferous cords that are solid & contain germ cells – contain a peripheral
layer of mesonephric derived cells that become Sertoli cells that surround a core of ~4 spermatogonia).
 Mesenchyme b/w cords develops into Leydig/Interstitial cells and also form CT septa that form lobules
in the testis.
o Lobules well developed in pigs, dogs, cats, less developed in ruminants, and contains smooth
muscle cells in horses.

 At puberty seminiferous cords become tubules and there is continuity b/w rete testis and efferent ducts.
 Mesonephric ducts develop into epididymis and ductus deferens
 Excurrent Extragonadal Duct System: carries sperm from gonad to urethra
o Efferent ducts
o Epididymis – makes seminal plasma
o Ductus deferens – transport tube & produces some fluid

Accessory Sex Glands

Prostate & Bulbourethral Glands develops from epithelial invaginations from urogenital sinus
Seminal Vesicles & Ampulla develops from epithelial evaginations from mesonephric duct

 Bull, Ram, Boar, Stallion have a full complement of sex glands


 Cat lacks seminal vesicles
 Dogs only have prostate

Testicular Descent
 Most mammals have testicular descent into scrotum
 Helps control temperature of the testis – puts testis outside body into cooler environment

Transabdominal Phase – ILGF-1 needed for ligament growth


 Retroperitoneal testes attached caudally to gubernaculum
 Peritoneal cells form junction w/ gubernaculum in inguinal region
 Gubernaculum grows toward and into scrotal region

Inguinal Scrotal Phase – Testosterone dependent


 Gubernaculum penetrates inguinal ring, and rapidly grows distally moving testes into the inguinal canal.
 Gubernaculum then shrinks pulling testes deeper into scrotum surrounding the testis in an inner visceral vaginal tunic
(also covers epididymis and spermatic cord), and an outer parietal vaginal tunic.
 Between tunics is a vaginal cavity that allows testes to freely move within scrotum.

Clinical Relevance
Samantha Bray 22
Cryptorchidism: failure of one or both testis to descend into scrotum. Common in humans. When bilateral it leads to sterility but testes
can still produce testosterone so secondary sex characteristics and behaviours are normal.

Inguinal Hernias: because the vaginal cavity and peritoneal cavity are continuous it is possible for structures like the inte stine to move
into the vaginal cavity through the inguinal canal. Can see coils of intestine under scrotum. Is surgically repairable – by pushing
intestine back into place and closing the inguinal canal. Potentially fatal is not fixed – SI can die and rupture leading to sepsis.

Genital System II

Female Gonad Development – XX

Without SRY protein expressed cells express female genes and inhibit male genes.
Dax-1 suppresses testes formation

Ovary Development
 Without SRY sex cord cells surround PGCs and become follicular cells. PGCs in ovary = oogonia
 Mesonephric duct regresses at same time as rete tubules
 Paramesonephric duct develops further and enlarges
 The follicular cells surrounding PGCs stay in the outer region of the ovary which later becomes the cortex.
 Sex cords disappear which forms a defined cortex and medulla regio n.
 Paramesonephric duct has an enlarged opening which will later become the infundibulum.

 Domestic Animals & Primates: follicles in cortex of ovary


o Cattle, Sheep, Pig: follicles randomly distributed in cortex
o Dogs, Cats: follicles are in clusters in cortex
 Horses: follicles are located centrally, and non-follicular region is at periphery. Ovary also “heart shaped” and has an
ovulation fossa that retains the coelomic epithelial covering & is where follicles ovulate from

Oogonia undergo mitotic divisions beginning in gestation, and ending during gestation or after birth.

Descent of Ovaries
 Posterior dislocation
 Dogs, Cats: ovaries hardly move & end up caudal to kidneys in sub -lumbar region
 Mare: ovaries b/w kidney & pelvic inlet
 Pigs, Cattle: descent is pronounced & ovaries much closer to pelvic inlet.
 Final position maintained by the suspensory ligament and proper ligament

Development of Female Repro Tract


 Paramesonephric ducts:
o Cranial part – infundibulum
o Caudal part – L and R ducts fuse and interact w/ urogenital sinus. Small bud evaginates from caudal part of
urogenital sinus and fuses with the fused paramesonephric ducts (mesoderm)  forms uterus, cervix and cranial
vagina.
o Vestibule originates from urogenital sinus by invagination from exterio r skin, and caudal vagina originates from
urogenital sinus (ectoderm)
 Epithelial buds from urethra and urogenital sinus form urethral and vestibular (mucous secreting) glands.

Formation of Supportive Structures


 Female gonads are retroperitoneal
 More caudally in the embryo the gonadal ridges and paramesonephric ducts move ventrally and rotate to a degree (do not
fuse).
 The fusion process of the paramesonephric ducts to produce the uterus (etc) causes the repro tract to sandwich b/w two layers
of peritoneum called the genital fold which becomes the broad ligament which supports the tract on dorsal & lateral aspects.

External Genitalia
Female – induced by estrogens
 Mesenchyme from primitive streak move around cloacal membrane and forms two cloacal folds.
 Folds fuse ventrally to form genital tubercle which becomes the clitoris.
 Folds subdivide into anal and urogenital membranes.
 Mesoderm lateral to urogenital fold proliferates and creates genital swellings that become labia.
Samantha Bray 23
Males – induced by androgens
 Genital tubercle elongates into phallus.
 Urogenital folds are lateral to urethral plate which has an epithelial cord known as the urethral groove. The folds fuse
enclosing the urethra  forms penile urethra
 Urethral plate does not extend to tip of penis – ectoderm invaginates into tip of penis and fuses with endodermal cells lining
penile urethra then canalizes allowing urethra to open at tip of penis.

Mammary Glands
 Arise along two ventral epidermal thickenings – mammary ridges that extend from axilla to inguinal region.
 # of glands that develop is species dependent
 Ridges develop into primary mammary buds – epidermal tissue penetrates mesenchyme (dermis). It becomes a secondary
mammary bud when the bud starts branching further penetrating the dermis. Secondary bud continues to grow during
embryonic life and canalizes at birth.
 Each gland has a lactiferous duct opening into larger ducts that empty from teat/nipple.
 During puberty and pregnancy is when a proper duct and alveolar system is constructed.
 Complete alveolar development occurs during last trimester of pregnancy in dams.

Genital System III

Clinical Relevance

Anomalies of Sexual Development

Turners Syndrome (Gonadal dysgenesis): XO chromosomal makeup. PGCs reach gonad but degenerate shortly after. Results
in hypoplastic ovary, small uterus, underdeveloped external genitalia. “Infantile” genitalia results from lack of gonadal
hormones. Prevalent in horses, also found in humans, pigs, dogs, cats

Klinefelter’s Syndrome: XXY – results from non-disjunction during Meiosis. Y chromosome results in male determining
genes being present – so male gonads form which produce male hormones thus individual develops phenotypically male.
Female chromosomes drives female genes which results in hypoplastic testes (& failure of spermatogenesis)  Sterility.
Found in humans, dogs, cats.

Hermaphroditism: XX – but one X is thought to have a translocated part of Y chromosomes w/ SRY gene. Thus, both ovarian
and testicular tissue present (ovotestis – both in single organ). Reported in all domestic animals – very rare.

Pseudo-hermaphroditism – Chromosome makeup and gonadal sex agree. External genitalia unclear. Male form more common.
Is a more common condition in dogs and pigs.

Abnormalities of Uterus/Vagina: Irregular fusion of paramesonephric ducts can result in varying types of uterus. Can get 2 uteru s w/ 2
vagina, a unicornuate uterus, or lack of cervix.

Hypospadias: urethra opens on ventral surface of penis rather than at the glans. Results from failure of the urethral groove to close in
the male. Potentially inheritable in some dogs. Length of opening can vary.

Placenta I

Ruminants and Pigs – have an anchor shaped placenta.


Horses and Carnivores – have a round shaped placenta.

Placenta – is a transient endocrine organ that produces hormones that enter maternal & fetal blood supply. During gestation it produces
progesterone and takes over the function of the CL in some spp. Produces enough progesterone that the CL can be removed w/o
detriment to pregnancy maintenance. It is made of fetal and maternal tissues:
 Chorioallantoic: chorion and allantois – Eutherians.
 Choriovitelline: chorion and yolk sac – Transient in most domestic animals  choriovitelline placenta replaces with
chorioallantoic at about wk 7 of equine pregnancy.
 Endometrium

Major Functional Unit: chorionic villi – projections on surface of chorion that interact w/ maternal tissue.
Samantha Bray 24

Placenta Classification: 2 ways.

1. Based on Chorionic Villi Distribution

 Diffuse: chorionic villi located over entire uterine luminal epithelium.


o Pig: closely space chorionic villi
o Horse: chorionic villi organized into microcotyledons which are distributed over the entire surface of chorion. Horses
also have endometrial cups that are derived from a thick tropohoblas band that develops around the fetus called
chorionic girdle (~d 25), girdle peels off fetal membranes and trophoblast invade endometrium and forms the cups
that produce eCG that aids in follicle maturation (~d 40). Cups later destroyed by maternal immune attack (~d 70).

 Cotyledonary: chorionic vascularized villous trophoblasts called cotyledons and endometrial caruncles come together as a
“spot weld” called a placentome. Eg. Ruminants.
o ~ d 30-36 villous processes of trophoblast form in chorioallantoic membrane opposite to caruncle tissue. Branching
of villi helps trophoblast fit into caruncle tissue.
o Placentomes can be convex (cow, giraffe) or concave (sheep, goat).

 Zonary: invasive band of chorion surrounds middle of fetus. Eg. Dog and cat.
o Inner transfer zone: region of exchange.
o Outer pigmented zones: site of hematomas and blood pooling & is important for ion transport.

 Discoid: disc like structure of chorion interacts w/ maternal tissue. Eg. primates and rodents.
o Chorion can invade up to 1/3 of maternal musculature.
o Humans have 2 villi types:
 anchoring villi that bury into uterine wall and anchor it.
 Floating villi – for absorption.

2. Based on Cell Layers at the Maternal Fetal Interface

 Epitheliochorial – least invasive, chorionic villi and uterine luminal epithelium are intact.
o Sow - no erosion of luminal epithelium.
o Mare – only chorionic girdle trophoblasts transiently & moderately invade epithelium.

 Synepitheliochorial – binucleated giant trophoblast cells (BNGC) migrate into uterine epithelium.
o Cows – short-lived trinucleated cells formed
o Sheep – continued production of BNGC can produce an extensive fetal-maternal syncytial layer

 Endotheliochorial – trophoblasts move through uterine epithelium & stroma and make contact w/ maternal endothelium.
o Cats, Dogs, Insectivores.

 Hemochorial – highly invasive, trophoblast passes through uterine epithelium, stoma & endothelium and comes into direct
contact with blood.
o Primates, Rodents.

Function During Pregnancy


 Respiratory exchange – O2 and CO2
 Fetal nutrition
 Excretory functions – water balance, pH control
 Hormone/Enzyme Production
 Immune Functions

Transport
 Simple diffusion of gases & simple molecules (drugs)
 Facilitated diffusion of glucose (uses gradient)
 Active transport of aa, vitamins (maintains high [] in fetus compared to mom)
 Receptor mediated endocytosis of igG, protein, fat, viruses
 Leakage – intact cells
Samantha Bray 25
Umbilical Cord – connects fetus to placenta. Made of fetal mucoid CT that surroudns 2 umbilical arteries and veins, the urachus, and
vestige of yolk sac. Umbilical a. spiral around the urachus and branches to amniotic sac and ends in chorionic membrane.
 Length by spp: Cat < Dog < Pig < Sheep < Cow < Human < Horse

Head and Neck I

Head
 Development involves CT and skeletal structures that are neural crest origin.
 Key feature is development of pharyngeal arches ~3rd week of gestation.
 Pharyngeal arches: develop men neural crest cells migrate into head and neck regions where they aggregate into 6 pairs of
arches. The 5th and 6th are rudimentary.

1st pharyngeal arch divides into maxillary and mandibular process and is caudal to the oropharyngeal membrane that seals off the
foregut.

Face Development
 Primordia form from proliferation of neural crest derived mesenchyme  forms 1 fronto-nasal prominence, 2 nasomedial
processes, 2 nasolateral processes, 2 maxillary prominences and 2 mandibular prominences.
o Fronto-nasal prominances develop into 2 pairs of ectodermal thickenings: lens placodes and nasal placodes.
o Maxillary prominences grow and extend medially and fuse w/ Nasomedial processes and forms the maxillary process
(future maxilla), primary palate, and tissues of upper lip.
 Upper lip may or may not have philtrum depending on degree of fusion which is spp. dependent.
o Mandibular prominences also fuse and form the lower jaw.
o In early stages – there is a deep Naso-lacrimal groove b/w the maxillary and nasal prominances. The groove extends
towards the eye and the floor of the ectodermal groove loses contact w/ surface and forms a canalized cord of cells –
the nasolacrimal (tear) duct.

Clinical Relevance: when fusion of nasomedial processes and maxillary prominences does not occur properly the philtrum is not
formed properly and results in cleft lip (also assoc. with cleft palate).

Nasal Cavities & Palates


 Nasal pits deepen and form L and R sacs separated by a septum, and separated from oral cavity by oronasal membrane (which
forms primary palate).
 Common nasal cavity forms at caudal end of nasal sacs and caudal part of primary palate atrophies – leaving a maxillary
process.
 The choana is the opening b/w the nasal and oral cavity.
 Palatine processes grow from lateral walls of nasal cavity. With growth of the oral cavity there is expansion of palatine
processes and fusion at midline forming a secondary palate.
 The secondary palate fuses with maxillary process. Small spaces in the palate remain and are called incisive foramina &
allows fluid to escape from oral cavity to vomeronasal organ and olfactory epithelium of nasal cavity.

Conchae
 Laminae projects from lateral walls of nasal cavity and form conchae.
 Have mesoderm core and covered w/ ectoderm that ossify into turbinate bones.
 Nasal cavity becomes divided into 3 passages – dorsal, middle, and ventral meatus.

Secondary Palate
 Degree of fusion b/w nasal septum and secondary palate helps to determine the communication b/w the pharynx and nasal
cavities.
o Horses – fusion is along the entire length – thus each nasal cavity communicates separately w/ pharynx
o All other domestic spp – fusion not so extension – nasal cavities have a common opening into nasopharynx.
 Secondary palate is membranous initially but ossifies in its first 2/3 and is known as the hard palate. The portion that rema ins
membranous projects into the pharynx and divides the pharynx into oral and nasal parts – called the soft palate.

Clinical Relevance

Cleft Palate: congenital malformation, rare in domestic animals, can be primary or secondary. Results in difficulty suckling and milk
drips from the nostrils.
 Primary: incomplete fusion of nasomedial processes w/ maxillary prominences
 Secondary: incomplete fusion of lateral palantine processes – leaving opening b/w oral and nasal cavities.
Samantha Bray 26

Oral Cavity: Teeth


 Domestic mammals have 2 forms of dentition: deciduous and permament teeth  thus these animals are Diphyodonts
 Teeth can be classified as incisor, canine, premolars or molar based on shape, function & location.
 Teeth can also be classified as either Brachyodont & Hypsodont

Brachydont – has a crown, root, and a narrowed neck at the gum line b/w the root and crown.

Hypsodont – has a body and a short root. The body protrudes above the gum line and also has a long portion that is embedded (in
young animals). Is produced from a LONG enamel organ – which is why there is more enamel below the gum line. Enamel organ also
folded leading to ridges on lateral and medial surfaces of teeth. Dental sac also lasts longer – thus cementum surrounds the tooth and
covers enamel – gives it a tougher occlusal surface.

Tooth Development (~9 slides)

 Fused maxillary and mandibular prominences are large pieces of undifferentiated tissue that begins to ossify.
 Thickened bands of jaw ectoderm form labio-gingival plates.
 The centre of the plates disintegrates and leaves a labio-gingival groove dividing tissue into primordia of the lips and gums.
 Tooth development is initiated by interaction b/w ectoderm of dental lamina and the underlying neural-crest derived
mesenchyme. Along the length of the dental lamina, ectodermal projections (dental buds) push into mesenchyme – driven by
expression of LEF-1 from mesenchyme
 Buds become cap-shaped and has inner and outer layers separated by stellate reticulum. Mesenchyme under the cap is the
dental papilla.
 Cap grows and then becomes bell-shaped & is called an enamel organ.
 Buds of permanent teeth are initiated from cords of cells.
 The cord connection b/w surface epithelium and bell-shaped developing tooth atrophies.
 Reticular cells induce inner epithelial layer to become ameloblasts (makes enamel).
 Mesenchyme under dental papilla develop into odontoblasts.
 Small group of ectodermal cells in inner epithelial layer of enamel organ (near apex of papilla) will form a knot (clump of
non-dividing cells).
 Knots act as signalling centre to regulate tooth shape by producing FGF-4, BMP2 and BMP4 & specifies the site of cusp
formation.
 Ameloblasts extend down sides of base of the developing crown.
 Odontoblasts make predentin at tip of papilla which later mineralizes to form dentin.
 Core of dental papilla becomes pulp cavity of tooth & dentin induces ameloblasts to produce more enamel (+ve feedback
mechanism).
 Shape of tooth crown occurs as dentin and enamel are formed (from apex to base of enamel organ). Base of the organ is the
junction of crown and root.
 A tube-like epithelial root sheath within the mesenchyme forms from extensions of inner and outer layers of enamel organ
 Dental sac has inner cells that become cementoblasts that produce cementum and become entrapped & become cementocytes.
 Osteoblasts form from outer layer of dental sac – produce bone that helps anchor tooth to jaw.
 Middle layer of sac becomes periodontal ligament.
 Eruption of teeth through gums is associated w/ root development but is not clearly u nderstood. The crow erupts through oral
epithelium. Enamel production stops (ameloblasts lost) when crown is formed and leftover enamel organ is shed.
 Odontoblasts remain through life and produces dentin.

Clinical Relevance

Anodontia: absence of teeth, rare. Due to failure of dental lamina or dental papillae to develop and induce tooth development.

Oligodontia – reduced tooth number

Polydontia – excessive teeth.

Delayed Shedding of Deciduous Teeth: common, secondary to failure of the periodontal ligament to detach from deciduous toot.
Permanent teeth erupt in front of deciduous teeth.

Enamel Lesions: occurs in large and small animals, due to malnutrition, infections (dog distemper), trauma. Can have pitted e namel or
complete lack of enamel w/ incomplete tooth development. Can coat the teeth w/ resin to protect teeth.
Samantha Bray 27
Head and Neck II: Pharynx, Thyroid, Tongue

Pharyngeal Arches
 Begin to develop ~ 3rd week of gestation
 Neural crest-derived cells migrate to head/neck region and aggregate forming 6 pairs of pharyngeal arches.
 Invaginations of ectoderm form b/w adjacent arches – called pharyngeal clefts.
 Endoderm of foregut evaginates b/w the arches – producing pharyngeal pouches.
 Contact of clef and pouches forms pharyngeal membranes.

Each Pharyngeal Arch has:


 Aortic arch artery
 Muscle component  comes from paraxial mesoderm
 Branch of cranial nerves

Aortic Arches – arises from mesoderm within each pharyngeal arch and forms vascular link to aortic sac and paired dorsal aortae.
Cranial caudal body folding results in cranial part of dorsal aorta bending and forming aortic arches lateral to the foregut. Aortic arches
develop sequentially. Aortic arches eventually form internal and external carotids, subclavian arteries and pulmonary arteries.

Pharyngeal Complex

Arches:
 2nd arch  gives rise to Stapes & bones of hyoid apparatus
 3rd arch  gives rise to other hyoid bones & stylopharyngeus muscle
 4th – 6th arches  laryngeal cartilages

Pouches:
 Endodermal epithelium of pouches differentiates into lymphatic and endocrine components.
 1st pouch  auditory tubes & tympanic cavity.
o Horses – diverticula of auditory tubes leads to development of Guttural Pouches.
 Guttural pouches are mucous secreting sacs that communicate w/ pharynx – may control BP in internal
carotids & also may play a role in cerebral blood cooling system.

 2nd pouch contains aggregate of tissue  palatine tonsils
 3rd & 4th pouches develop into parathyroid glands.

Thyroid Development
 develops as ventral midline endodermal diverticulum on floor of pharynx
 structure becomes bilobar and moves caudally and ends up ventral to developing trachea.
 Isthmus not constant b/w spp:
o Pigs/Primates – isthmus large and forms a medial lobe
o Cattle – isthmus is small band b/w lobes
o Horses – poorly defined
o Small Ruminants – band of CT
o Cats & Dogs – isthmus absent

Caudal migration of thyroid causes parathyroid IV to embed in the thyroid gland. Parathyroid III glands are caudal to thyroid
(& not present in pigs). Parathyroid glands produce PTH which increases blood calcium levels.

Thymus Development
 Initially 2 tubular structures
 Extends caudally & fuse in midline and associate w/ pericardium
 Produces thymic hormones responsible for making competent T-lymphocytes.

Clefts:
 1st cleft  epithelial lining of external auditory meatus.
 2nd pharyngeal arch extends caudally over the 2nd & 3rd clefts – a transient structure lined by ectoderm then forms cervical
sinus.

Tongue
 3 elevations form at region of 1st pharyngeal arch due to underlying mesenchyme growth.
Samantha Bray 28
o 2 lateral lingual swellings
o 1 tuberculum impar
 Copula develops at 2nd pharyngeal arch
 Hypopharyngeal eminence forms around 3rd & 4th pharyngeal arch.
 Most of the tongue is covered in stratified squamous epithelium of endodermal origin except at apex where tongue has
ectodermal components.
 In carnivores and humans the tuberculum impar is minimally involved in tongue development
 Ungulates have a tuberculum impar that significantly contribute to dorsal aspect of tongue forming the torus linguae.
 Root of tongue is from the growth of the hypopharyngeal eminence that grows over the copula (which atrophies) – epithelium
covering is derived from endoderm.

Pituitary Gland
 Ectoderm – both neural and oral help form pituitary
 Upward evagination of ectoderm in midline of roof of stomodeum forms adenohypophyseal pouch (forms anterior lobe of
pituitary).
 Ventral diverticulum in floor of brain forms – infundibulum (posterior lobe of pituitary).
o Infundibulum forms  hypophyseal stalk and pars nervosa.
 Cleft forms within adenohypophysis.
 Dorsal part of adenohypophysis grows around stalk of infundibulum  becomes pars tuberlis
 Rostral part continutes growth  becomes pars distalis
o Pars distalis develops into endocrine cells (acidophils, basophils, chromophobes)
 Caudal part of adenohypophyseal vesicle  pars intermedia
o Pars intermedia has large pale staining cells that produce melanocyte stimulating hormone (MSH).
 Neuron processes move from paraventricular and supraoptic nuclei into stalk and extend into pars nervosa where they secrete
oxytocin and ADH
 Species Differences:
o Domestic species – intermedia in direct contact w/ infundibulum & fuse.
o Pigs, Carnivores, Horses – pars intermedia encloses around the pars nervosa
 Horses – missing the adenohypophyseal cleft
o Ruminants – small amount of pars distalis on rostral surface. Pars intermedia does not extend around the pars
nervosa.

Head and Neck III – Eye and Ear

FINAL EXAM: mostly multiple choice, some long answers (w/ choice of questions). 50% on last 5 lectures (placenta, head and
neck I & II), 10% on teratology, 10% test 1, 10% test 2, 10% test 3.

THE END

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