Subject: Surgery Topic: Neuroembryology Date: 11.11.2009 Lecturer: Dr. A. Jasbson Transcriber: Bean Subject Head: ECG No.

of Pages: 7 OUTLINE . . . . . Development of the Central Nervous System CNS Development Early Embryogenesis Neurulation Differentiation of the Neural Tube (Anterior/Posterior) idea of what was discussed . Disorders in Neurulation yahugrups . Prosencephalic Development . Neuronal Proliferation . Neuronal Migration . Myelination
References: powerpoint/ recording

This transcription is to give you an Reviewer for the completion: To follow sa

langmans embryology yung iba

NEUROEMBRYOLOGY
I. Development of the Central Nervous System (COMPONENTS) - There are two components in the development of the human nervous system: . External Development - Neural part of EMBRYOGENESIS - Occurs within the 1st 6 weeks of gestation . Internal Development - Neural part of FETAL DEVELOPMENT - Takes place After the 1st 6 weeks of gestation (or after the external development) II. CNS Development (EVENTS) Major Events in CNS Development Developmental Event Primary neurulation Prosencephalic development Neuronal proliferation Neuronal migration Organization Myelination EARLY EMBRYOGENESIS

Takes place during 3-4 weeks of gestation 2-3 mos of gestation 3-4mos of gestation 3-5 mos of gestation 5mos to yrs postnatal Birth to yrs postnatal

III.

A.

One of the main tasks of early embryogenesis is to lay out the body plan of the organism:

A-P axis the body should have a determined anteroposterior axis during development, which serves as the main landmark for proper embryogenesis Define the midline the midline is a landmark for lateralization. Remember that the CNS is a midline structure, and this should be established in the early embryonic life It is important that these landmarks are determined before the formation of the CNS. (cge nga, isipin mo kung
walang AP axis eh nasa likod ung isang mata mo at kung walang midline, nasa tagiliran mo spinal cord mo)

B. The nervous system begins to develop at a relatively late stage in embryogenesis. C. Inductive signal controls cell differentiation (important in neural tissues) Neuroembryology Page 1 of 9

Two major groups of factors: 1. Inducing factors

2. Surface receptors

signaling molecules provided by other cells (non neural)

Molecules that are activated or induced in cells upon exposure to an inducing factor from another cell.

His next topic is gastrulation. However, in the book, before that should be the formation of the bilaminar germ disc Bilaminar Embryonic Disc Forms in the 2nd week of embryogenesis Remember doc Arties lecture? This is the week of TWOs o 2 Cavities formed Chorionic Cavity + Amniotic Cavity o The trophoblast divides outer cytotrophoblast + inner syncytiotrophoblast o 2 Cell Layers form from the inner cell mass Epiblast + Hypoblast D. Gastrulation (days 14-19) Occurs in the third week of gestation Quickie lang: from the bilaminar germ disc, a primitive streak forms on the epiblast (thus, creating the first midline structure). Cells of the epiblast migrate on the direction of the streak. Upon doing so, cells become more compacted and flask-shaped. They then detach from and slip beneath the epiblast forming a third cell layer. This process is called INVAGINATION. The trilamiar embryonic disc is now formed. Trilaminar Embryonic Disc The. now becomes the which will become the Epidermis* Hair, nail, sweat glands Central and peripheral nervous system* Lens Sensory epithelium of nose, eye, ear Mammary gland Pituitary Tooth enamel Skeletal and cardiac muscle* Connective tissue* Blood and vascular system* Skeleton Genitourinary system except bladder Dermis Spleen Adrenal cortex Gastrointestinal tract* Pancreas Liver* Lungs* and airways (including The respiratory epithelium in the middle ear and nose) Urinary bladder Thyroid Parathyroid Thymus

Epiblast Layer

ECTODERM

Invaginated Epiblasts (Mesoblast)

MESODERM

Hypoblast Layer

ENDODERM

*are the only ones he specified

Neuroembryology Page 2 of 9

CEPHALIC/CRANIAL END

Cranial end of the streak Primitive knot/Hensens

CAUDAL END

1. Key events: a. Formation of Primitive Streak - Induces formation of germ layers b. Formation of notochord - Defines the midline and the basic body plan - Induces formation of nervous system

2.

Day 14-16 (in the primitive streak) - Cranial end thickens (Primitive knot or Hensen's node) - Primitive groove forms in the middle of the primitive streak

3. Day 16 - Cells of the Epiblast migrate into the primitive groove (Migrate towards the groove to form the mesoblast intraembryonic mesoderm) (Some mesoblast cells invade hypoblast and displace these cells laterally extraembryonic mesoderm) - Remainder of cells in epiblast embryonic ectoderm

4.

The Primitive Streak - Regresses into an insignificant structure in the sacrococcygeal area - Clinical Note: these pluripotent cells may give rise to Sactococcygeal Teratoma

5. Notochord - A distinct cylinder of mesodermal cells - Specifies the basic topography of the embryo and acts as a rigid axis around which the embryo develops - Determines the position of the nervous system and is required for its subsequent differentiation - Notochord sends inductive signals to the overlying ectoderm (causes a subset of ectodermal cells to differentiate into neural precursor cells which thicken into a distinct columnar epithelium called the Neural Plate) (This process is called Neurulation) - Fate: Will mostly degenerate persisting only as the nucleus pulposus - Clincal Note: Notochordal remnants give rise to such pathologies as intervertebral disc herniations and chondromas. Rarely, the neurenteric canal may persist and result in a link between the central canal of the spinal cord and the intestine- Spinal-Enteric Fistula Neuroembryology Page 3 of 9

IV.

NEURULATION A. Formation of the neural plate, the neural folds, and their closure to form the neural tube. 3 cardinal features of morphogenesis: 1. Polarity - Wide end lies rostrally brain - Narrow end lies caudally- spinal cord 2. Bilateral Symmetry 3. Regionalization - differentiation in a rostral-caudal direction B. Types of Neurulation 1. Primary Neurulation (Dorsal Induction) - inductive events in a dorsal aspect of the embryo resulting in the formation of brain and spinal cord, including segments of only up to the lumbar region. 2. Secondary Neurulation (Ventral Induction) - exclusive to lower sacral segments of the cord (caudal neural tube formation, which occurs later)

C. Primary Neurulation - CNS begins on dorsal aspect of embryo as a plate of tissue in the middle of the ectoderm; underlying notochord and chordal mesoderm induce formation of neural plate at 18 days. - Neural tube - first folds (neural folds) occurs at lower medulla at 22 days; closure proceeds rostrally and caudally, but it is not a simple zipper like process - Anterior end of NT closes at 24 days, posterior end at 26 days; posterior site of closure at lumbosacral level; more caudal segments formed by different process - Formation of brain and spinal cord:

1. 2.

Day 18 Neural Plate invaginates (Edges- neural folds ; Depth- neural groove which

skins below ectoderm)

Day 21-23 groove begins to close forming the neural tube

3. Closure of the Neural Tube - Closure of the remaining tube occurs over 4-6 days and keeps pace with the cranial to caudal development of the somites Parallel to this process: Cutaneous ectoderm separates from the neurectoderm to form the overlying skin Lateral mesoderm migrates between the two ectodermal layers to form the posterior vertebral arches - Clinical Note: Any disruption between when the neural plate begins to fold and when it fuses to form the neural tube leads to craniorachiscisis, the most severe Neural Tube Defect a. Closure of Anterior Neuropore (Day 23-25): - Proceeds from both directions: From the rhombencephalon caudally From the future optic chiasm cranially - Site of final closure is the commissural plate which is immediately anterior to the lamina terminalis at the site of the future anterior commissure - Failure Anencephaly b. Closure of Posterior Neuropore (Day 25-27) Proceeds craniocaudally Site of closure is roughly opposite somites 30/31 (~S2 level ) Failure Myelomeningocoele, Meningocoele

Neuroembryology Page 4 of 9

NEURAL TUBE CLOSURE DEFECTS: CAUDAL There are two kinds of closure defect in the primary neurulation Open Neural Tube Defects Meningocoele Meningomyelocoele Closed: Neural Tube Defects Tethered Cord Spinal Lipomas Split Cord Malformations Sacral Teratomas . Secondary Neurulation - Further neural development occuring caudal to the posterior neuropore, after termination of primary neurulation - Formation of caudal Neural Tube (lower sacral and coccygeal segments) occurs by sequential canalization (4-7 wks gestation) and retrogressive differentiation (7wks - birth+) - At 28-32 days, aggregate of undifferentiated cells at caudal end (caudal cell mass) develop vacuoles. They enlarge coalesce and make contact with central canal; accessory lumina may remain - Remaining structures are ventriculus terminalis (in the conus) and filum terminale - Primitive streak has regressed, and forms a pluripotent mass of cells called the caudal eminence or end bud (Forms conus medullaris and filum terminale) V. Differentiation of the Neural Tube (Anterior/Posterior) Three primary brain vesicles has now formed and this is patterned as a result of the expression of the HOX gene The Main Vesicles of the Neural Tube and their Future Forms
Three-vesicle Stage 1. Forebrain (Prosencephalon) Five-vesicle Stage Telencephalon (endbrain) Diencephalon 1. 2. Major mature derivatives Cerebral cortex, basal ganglia, hippocampal formatin, amygdala, olfactory bulb Thalamus, hypothalamus, subthalamus, epithalamus, retina, optic nerves and tracts optic cup and stalk, pituitary, and epiphysis (pineal) Midbrain Pons and cerebellum Medulla Spinal cord Related Cavity Lateral ventricla Third ventricle

2. Midbrain (Mesencephalon) 3. Hindbrain (Rhombencephalon)

Mesencephalon (midbrain) Metencephalon (afterbrain) Myelencephalon (medullary brain) Caudal part of neural tube

3. 4. 5. 6.

Cerebral aqueduct Fourth ventricle Fourth ventricle Central canal

4. Caudal part of neural tube

VI. DISORDERS IN NEURULATION A. In order of decreasing severity 1. Craniorachischisis totalis a.Anencephaly with a contiguous spinal defect involving at least the cervical spine - the most severe of the neural tube defects b.There may be a neural plate like structure, but no axial skeleton or dermal covering c. Onset no later than 20-22 days d.Most aborted; some to early fetal stages Neuroembryology Page 5 of 9

2. Anencephaly a.Defect is failure of anterior neural tube closure (day 23-25) b.Most severe case - defect from level of lamina terminalis to foramen magnum (holocrania, holoanencephaly); c. if defect does not extend to foramen magnum meroacrania, meroanencephaly 3. Myeloschisis 4. Encephalocele a.Restricted disorder of neurulation, involving anterior neural tube closure b.70-80% are occipital; frontal encephaloceles may protrude into nasal cavity (more common in SE Asia) c. Low occipital encephaloceles may have deformities of brainstem, cerebellum in the encephalocele, and abnormalities of skull base and cervical vertebrae (Chiari III) d.Timing around 26 days (time of closure of anterior neural tube) e.Distinguished from anencephaly because they have an epidermal covering over the cranial neural tube closure defects Anterior Cranial Fossa Encephaloceles Epidemiology Very common in Southeast Asia where they are 9 times more common than convexity encephaloceles Most are sporadic lesions CLINICAL FINDINGS - Apparent mass lesion - CSF leak - Obstructed nasal breathing - Meningitis - Snared nasal polyp - Hypertelorism - Hydrocephalus Associated cephalic anomalies - Cleft lip and palate - Malformed nasal tip - Microphthalmia - Corneal opacity - Coloboma - Agenesis or lipoma of the corpus callosum RADIOLOGY - Bony defect by CT - CNS anatomy by MRI - Vascular anatomy by MRA or angiography Outcome - Surgery successful at preventing CSF leak and meningitis - Nasal obstructive breathing reduced - Cosmetic results are satisfactory - Patients with hydrocephalus fare poorly

5. Myelomeningocele/Chiari malformation VII. PROSENCEPHALIC DEVELOPMENT A. Peak time period (2-3 months) B. Major Events 1. Prechordal mesoderm face & forebrain Prosencephalic development Prosencephalic formation Prosencephalic cleavage paired optic and olfactory structures Telencephalon cerebral hemisphere Diencephalon thalamus & hypothalamus Midline Prosencephalic development corpus callosum,septum pellucidum, optic nerves chiasm, hypothalamus Neuroembryology Page 6 of 9

C. Disorders of Prosencephalic Development 1. Prosencephalic Formation a.Aprosencephaly b.atelencephaly 2. Prosencephalic cleavage a.Holoprosencephaly b.Holotelencephaly 3. Midline Prosencephalic development a.Agenesis of the corpus callosum b.Agenesis of the septum pellucidum c. Septo-optic dysplasia d.Septo-optic-hypothalamic dysplasia VIII. NEURONAL PROLIFERATION A. Peak time period (3-4 months) B. Major Events - VZ & SVZ are the sites of proliferation - proliferative units are produced by symmetrical division of stem cells - proliferative units later enlarge by asymmetrical divisions of stem cells before neuronal migration C. Disorders of Neuronal Proliferation 1. Diminished number of proliferative units a.Radial Microbrain 2. Diminished size of proliferative units a.Microcephaly vera 3. Isolated Macrencephaly IX. NEURONAL MIGRATION A. Peak Time Period 3-5 months B. Major events 1. Cerebrum a.Radial Migration : cerebral cortex, deep nuclei 2. Cerebellum a.Radial Migration : Purkinje cells, dentate nucleus b.Tangential Migration : external internal granule cells C. Selected Key molecular Determinants of Neuronal Migration 1. How do the migrating cells know how to reach where they are going? a.Radial Glial cells -serves as guides to migrating neuroblasts -facilitate development of columnar organization of cerebral cortex -undergo mitosis and transformation to astrocytes b. Preplate neurons marginal(Cajal Retzius) subplate neurons Radial Glial Migrating neurons Fibronectin, chondroitin and Heparan sulfalte proteoglycan Reelin , platelet activating factor GABA receptors Laminin , erb B4 receptors Neuregulin, astrotactin, double Cortin, Filamin1, Cyclin dependent kinase 5, Ca channels N methyl aspartase receptors

2. Migration to the Cerebral Cortex a.Neurons migrate following radial glial guides b.Proliferative units of VZ migrate via radial glial scaffolding to become the ontogenic neuronal colums of the cerebral cortex Neuroembryology Page 7 of 9

c. Early arriving neurons take deep positions in cortex and later arriving neurons take superficial positions (Cortical Neurons are generated in an inside-first, outside-last order.) D. Disorders of Neuronal Migration 1. 2. 3. 4. 5. Schizencephaly (abnormal slits, or clefts, in the cerebral hemispheres) Lissencephaly (lack of development of brain folds/gyri and grooves/sulci) Polymicogyria (excessive number of small convolutions/gyri on the surface of the brain) Heterotopia (displacement of gray matter into the cerebral white matter or ventricles) Focal cerebrocotical dysgenesis

X. NEURONAL ORGANIZATION A. Peak Time : 1. 5 months gestation years postnatal B. Major Events 1. 2. 3. 4. 5. 6. Subplate neurons establisment and differentiation Lamination - alignment, orientation and layering of the cortical plate neurons Neurite outgrowth dendritic and axonal ramification Synaptogenesis Cell death and selective elimination of neuronal processes and synapses Glial proliferation and differentiation

C. Disorders of Neuronal Organization 1. 2. 3. 4. 5. 6. XI. MYELINATION A. Peak Time : 1. Birth years postnatal B. Major Events 1. Oligodendroglial proliferation, differentation and alignment myelin sheaths C. Disorders of Myelination 1. Cerebral white matter hypoplasia 2. Amino or organic acidopathies 3. Hypothyroidism 4. Post natal under nutrition 5. Prematurity -END OF TRANSCRIPTIONFrom the transcriber: Greetings and salutations to Batch 2011! May God guide us through our path towards the medical profession and to become True Lasallian Doctors in the near future. We make our own choices and pave the path towards our life, and God guides us through His will, way, and time. God knows whats best for us. So Lord, Let Your Will be done. I also like to greet and salute batches 2010, 2012, and 2013! Ito na, Pagbati! Haha: First and foremost, I would like to greet my blockmates in BS Human Biology at DLSU. HB105! Still standing strong through Med Life: JV, Sarz, Darwin, Lem, Dianne Mae, KC, Jason Pete, Kenneth, Eka, Kit, Bianx, Claudio, Kyra, Jap P., Kath, Luis, Jen, Ronces, Nestor, Mavs, K-Ann, Geli. Athalyn, and Annie (Happy Birthday!). Of course, I wont forget Aisne, Suzanne, Karen, Patrick, and Valerie, we miss you guys! Greetings to NekLes, ElmerRache, Earl, MeanJay, Charlie, MonMon, Edsie, Christian, MarkJamie, Chek, and Dakila. Bati kela Twins Don and Gian, Roan, Cheli, JC, Carlo, Ivy, and Mitch. Hi to Big John & Riney, Jap A., Joem, Bobot & Abby, Arian, Zandro, Tope, and Anna Hello to Atha&Ryan, NJane, Ayks, Kenneth&Lyn, Daniel&Kat, Kevin, and Trisha. Greetings to the Ferrer Sisters, Noel, Val, Alex & Trish, Albert, and Noella. Hi to Shaula & Caruso, Izzie, Wedz & Pods, Chesca, Ann, Mia, and Long. Hello to Andrea, Hazel, Kate, Sarah K, and Nice Greetings to: Sixto, Rona, Em, Lyn G., Kuya Benjo, Victor, Chrysnel & Kath, Akuoma, and D.J. Hi to Presh, Aileen, Jenny, Phoebe, Adette, Nene, Min, and Docile. Hello to Shyn, MaeMae, Fatz, Reng, and Celeen.

Mental Retardation Down Syndrome Fragile X-Syndrome Angelman Syndrome Infantile Autism Duchenne muscular dystrophy

Neuroembryology Page 8 of 9

Greetings to Teen, Mars, Iya, and Kaye. Hi to my friends from Batch 2012 and 2013.

FROM THE SH: Sorry kung sobrang late ang tranks na to.. nabigay sakin Tuesday na sa ibang transcriber: sana kung on the week of the exams nyo ibibigay sa sh mga tranx nyo, sana ayos na, yung hindi copy paste lang na halatang halata sana gandahan nyo Dianne, kailangan talaga natin mag-usap para sa mga tranxer sa mga subs: sorry, gagawa ako ng isa pang reviewer para dito para sa mga extra notes di ko na nadagdagan kasi wala talagang kalaman laman the first 3 pages naayos ko pa sana lahat naayos ko din a ko aabot sa MRL sorry bean, next tym a

Neuroembryology Page 9 of 9