Neural System Development

Embryology - 5 Dec 2023        Expand to Translate
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Introduction

Neural groove closing to neural tube, early week 4
(Stage 10)

Relative brain size embryonic (week 4, 5, 6, and 8) and late fetal (third trimester)

Neural development is one of the earliest systems to begin and the last to be completed after birth. This development generates the most complex structure within the embryo and the long time period of development means in utero insult during pregnancy may have consequences to development of the nervous system.

The early central nervous system begins as a simple neural plate that folds to form a neural groove and then neural tube. This early neural is initially open initially at each end forming the neuropores. Failure of these opening to close contributes a major class of neural abnormalities (neural tube defects).

<html5media height="320" width="300">File:Stage 16 MRI 3D03.mp4</html5media>

Within the neural tube stem cells generate the 2 major classes of cells that make the majority of the nervous system : neurons and glia. Both these classes of cells differentiate into many different types generated with highly specialized functions and shapes. This section covers the establishment of neural populations, the inductive influences of surrounding tissues and the sequential generation of neurons establishing the layered structure seen in the brain and spinal cord.

• Neural development beginnings quite early, therefore also look at notes covering Week 3 - neural tube and Week 4 - early nervous system.
• Development of the neural crest and sensory (hearing/vision/smell) are only introduced in these notes and are covered in detail in other notes sections.

Some Recent Findings

Brain stem subdivisions Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates "Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here, we use RNA sequencing, cell imaging, and lineage tracing of mouse and human in vitro NSCs and monkey brain sections to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons. As human telencephalic NSCs develop from pluripotency in vitro, they transition through organizer states that spatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple human pluripotent lines vary in these early patterning states, leading differentially to dorsal or ventral telencephalic fates. This work furthers systematic analyses of the earliest patterning events that generate the major neuronal trajectories of the human telencephalon." Review - Time for Radical Changes in Brain Stem Nomenclature - Applying the Lessons From Developmental Gene Patterns "The traditional subdivision of the brain stem into midbrain, pons, and medulla oblongata is based purely on the external appearance of the human brain stem. There is an urgent need to update the names of brain stem structures to be consistent with the discovery of rhomobomeric segmentation based on gene expression. The most important mistakes are the belief that the pons occupies the upper half of the hindbrain, the failure to recognize the isthmus as the first segment of the hindbrain, and the mistaken inclusion of diencephalic structures in the midbrain. The new nomenclature will apply to all mammals. This essay recommends a new brain stem nomenclature based on developmental gene expression, progeny analysis, and fate mapping." Functional connectome of the fetal brain "Large-scale functional connectome formation and re-organization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated prior to birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function. The fetal to neonatal period is well known as a critical stage in brain development. In this study, we evaluate the network topography of normative functional network development during connectome genesis in utero Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction." neural Nervous System Regionalization Entails Axial Allocation before Neural Differentiation "Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This "primary regionalization" allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS." Evolution of the Human Nervous System Function, Structure, and Development "To better understand the molecular and cellular differences in brain organization between human and non-human primates, we performed transcriptome sequencing of sixteen regions of adult human, chimpanzee, and macaque brains."

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Neural System Development | Neural System Embryology | Neural Tube Closure | Neural Plate | Neuropore | Developmental Myelination | Neural Vascular Development | Cortical Plate

Older papers

These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. Secondary neurulation of human embryos: morphological changes and the expression of neuronal antigens "The morphological changes and expression patterns of neuronal antigens of human embryos, obtained from the therapeutic termination of pregnancy or from surgical procedures, were analyzed in order to characterize the secondary neurulation. ...The formation of the caudal neural tube to the tip of the caudal portion of the embryo was finished at stage 17. The postcloacal gut had completely disappeared at stage 18, and multiple cavities of the caudal neural tube were clearly visible. The caudal portion of the neural tube showed findings suggestive of involution at stage 19. The expression patterns of neuronal antigens were as follows: N-CAM and NeuN showed immunoreactivity at the germinal layer of the spinal cord at stages 17 and 18. Neurofilament-associated protein (3A10) showed persistent immunoreactivity at the caudal cell mass and notochord during the observation period, along with the spinal cord, and the positive reactions were mainly located at the dorsal white matter at stage 17. Synaptophysin showed a weak positive reaction at the caudal cell mass and notochord at stages 13 and 14, evident by staining observed at the spinal cord at stages 15 and 16. There was no definite positive reaction for GFAP." Neural induction and early patterning in vertebrates "Work on the molecular circuitry underlying neural induction, also in the same model system, demonstrated that elimination of ongoing transforming growth factor-β (TGFβ) signaling in the ectoderm is the hallmark of anterior neural-fate acquisition. This observation is the basis of the 'default' model of neural induction. Endogenous neural inducers are secreted proteins that act to inhibit TGFβ ligands in the dorsal ectoderm. In the ventral ectoderm, where the signaling ligands escape the inhibitors, a non-neural fate is induced. Inhibition of the TGFβ pathway has now been demonstrated to be sufficient to directly induce neural fate in mammalian embryos as well as pluripotent mouse and human embryonic stem cells." Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice "Proliferating neural stem cells and intermediate progenitors persist in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain. This extensive germinal layer in the walls of the lateral ventricles is the site of birth of different types of interneurons destined for the olfactory bulb. The cell cycle dynamics of stem cells (B1 cells), intermediate progenitors (C cells), and neuroblasts (A cells) in the V-SVZ and the number of times these cells divide remain unknown. Using whole mounts of the walls of the lateral ventricles of adult mice and three cell cycle analysis methods using thymidine analogs, we determined the proliferation dynamics of B1, C, and A cells in vivo." Dynamic imaging of mammalian neural tube closure "Here we use laser point scanning confocal microscopy of a membrane expressed fluorescent protein to visualize the dynamic cell behaviors comprising neural tube closure in the cultured mouse embryo. In particular, we have focused on the final step wherein the neural folds approach one another and seal to form the closed neural tube. Our unexpected findings reveal a mechanism of closure in the midbrain different from the zipper-like process thought to occur more generally. Individual non-neural ectoderm cells on opposing sides of the neural folds undergo a dramatic change in shape to protrude from the epithelial layer and then form intermediate closure points to "button-up" the folds. Cells from the juxtaposed neural folds extend long and short flexible extensions and form bridges across the physical gap of the closing folds." Apoptosis is not required for mammalian neural tube closure "Apoptotic cell death occurs in many tissues during embryonic development and appears to be essential for processes including digit formation and cardiac outflow tract remodeling. Studies in the chick suggest a requirement for apoptosis during neurulation, because inhibition of caspase activity was found to prevent neural tube closure. In mice, excessive apoptosis occurs in association with failure of neural tube closure in several genetic mutants, but whether regulated apoptosis is also necessary for neural tube closure in mammals is unknown. Here we investigate the possible role of apoptotic cell death during mouse neural tube closure. We confirm the presence of apoptosis in the neural tube before and during closure, and identify a correlation with 3 main events: bending and fusion of the neural folds, postfusion remodeling of the dorsal neural tube and surface ectoderm, and emigration of neural crest cells."

Objectives

Human embryo cortex (Week 8, Carnegie stage 22)

1. Understand early neural development.
2. Understand the formation of spinal cord.
3. Understand the formation of the brain; grey and white matter from the neural tube.
4. Understand the role of migration of neurons during neural development.
5. To know the main derivatives of the brain vesicles and their walls.
6. To know how the nervous system is modelled, cell death etc.
7. To understand the contribution of the neural crest.
8. Understand the developmental basis of certain congenital anomalies of the nervous system, including hydrocephalus, spina bifida, anencephaly and encephalocele.

Reading

UNSW Embryology

Citation: Hill, M.A. (2020). UNSW Embryology (20th ed.) Retrieved December 5, 2023, from https://embryology.med.unsw.edu.au Neural Links: ectoderm | neural | neural crest | ventricular | sensory | Stage 22 | gliogenesis | neural fetal | Medicine Lecture - Neural | Lecture - Ectoderm | Lecture - Neural Crest | Lab - Early Neural | neural abnormalities | folic acid | iodine deficiency | Fetal Alcohol Syndrome | neural postnatal | neural examination | Histology | Historic Neural | Category:Neural Neural Parts: neural | prosencephalon | telencephalon cerebrum | amygdala | hippocampus | basal ganglia | diencephalon | epithalamus | thalamus | hypothalamus‎ | pituitary | pineal | mesencephalon | tectum | rhombencephalon | metencephalon | pons | cerebellum | myelencephalon | medulla oblongata | spinal cord | neural vascular | ventricular | lateral ventricles | third ventricle | cerebral aqueduct | fourth ventricle | central canal | meninges | Category:Ventricular System | Category:Neural Week 4 | Neural System Development | Neural Crest Development | Integumentary Animal Neural Development - A number of different animal models of neural development, both normal and abnormal, have been established. Mouse | Pig | Rabbit | Chicken

The Developing Human: Clinically oriented embryology

Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders. (links only function with UNSW connection)

The Developing Human: Clinically Oriented Embryology (10th edn)  UNSW Students have online access to the current 10th edn. through the UNSW Library subscription (with student Zpass log-in). APA Citation: Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders. Links: PermaLink | UNSW Embryology Textbooks | Embryology Textbooks | UNSW Library Introduction to the Developing Human First Week of Human Development Second Week of Human Development Third Week of Human Development Fourth to Eighth Weeks of Human Development Fetal Period Placenta and Fetal Membranes Body Cavities and Diaphragm Pharyngeal Apparatus, Face, and Neck Respiratory System Alimentary System Urogenital System Cardiovascular System Skeletal System Muscular System Development of Limbs Nervous System Development of Eyes and Ears Integumentary System Human Birth Defects Common Signaling Pathways Used During Development Appendix : Discussion of Clinically Oriented Problems Chapter 3 Week 3 Chapter 17 Nervous System

Larsen's human embryology

Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone. (links only function with UNSW connection)

Larsen's Human Embryology (5th edn)  UNSW students have full access to this textbook edition through UNSW Library subscription (with student Zpass log-in). APA Citation: Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone. Links: PermaLink | UNSW Embryology Textbooks | Embryology Textbooks | UNSW Library Gametogenesis, Fertilization, and First Week Second Week: Becoming Bilaminar and Fully Implanting Third Week: Becoming Trilaminar and Establishing Body Axes Fourth Week: Forming the Embryo Principles and Mechanisms of Morphogenesis and Dysmorphogenesis Fetal Development and the Fetus as Patient Development of the Skin and Its Derivatives Development of the Musculoskeletal System Development of the Central Nervous System Development of the Peripheral Nervous System Development of the Respiratory System and Body Cavities Development of the Heart Development of the Vasculature Development of the Gastrointestinal Tract Development of the Urinary System Development of the Reproductive System Development of the Pharyngeal Apparatus and Face Development of the Ears Development of the Eyes Development of the Limbs Chapter 4 Week 4 Chapter 9 Development of the Central Nervous System Chapter 10 Development of the Peripheral Nervous System

Neural Movies

Neural Development
‎‎Neural Plate Page | Play	‎‎Neural Tube Page | Play	‎‎Secondary Neurulation Page | Play	‎‎Stage 13 Neural Page | Play	‎‎Embryo CNS Page | Play	‎‎Neural Tube Close Page | Play
‎‎Embryo CNS Page | Play	‎‎Embryo Stage 16 Page | Play	‎‎Stage 17 Embryo Page | Play	‎‎Stage 22 Neural Page | Play	‎‎Embryo CNS Page | Play	‎‎Sagittal Head Page | Play
		Abnormalities Ultrasound
‎‎Sylvian Fissure Page | Play	‎‎Adult Brain Page | Play	‎‎Dandy-Walker Page | Play	‎‎Spina Bifida Page | Play		‎‎Neural Page | Play

Links: Movies | Postnatal - Neural Examination Movies

Early Neural Development

Adult human brain

The stages below refer to specific Carneigie stages of development (modified from O'Rahilly and Müller 1994).

Early Neural Timeline
Carnegie Stage	Event
8	(about 18 postovulatory days) neural groove and folds are first seen
9	three main divisions of the brain, which are not cerebral vesicles, can be distinguished while the neural groove is still completely open.
10	(two days later) neural folds begin to fuse near the junction between brain and spinal cord, when neural crest cells are arising mainly from the neural ectoderm
11	(about 24 days) the rostral (or cephalic) neuropore closes within a few hours; closure is bidirectional, it takes place from the dorsal and terminal lips and may occur in several areas simultaneously. The two lips, however, behave differently.
12	(about 26 days) The caudal neuropore takes a day to close. The level of final closure is approximately at future somitic pair 31 (corresponds to the level of sacral vertebra 2). Secondary neurulation begins, is the differentiation of the caudal part of the neural tube from the caudal eminence (or end-bud) without the intermediate phase of a neural plate.
13	(4 weeks) the neural tube is normally completely closed.
Links: neural | Week 3 | Week 4

Week 4 to Week 8

Embryonic Central Nervous System
Stage 13	Stage 14	Stage 16	Stage 21
scale bar = 1 mm
Week 4	Week 5	Week 6	Week 8

Week 4 - Stage 13

<html5media height="420" width="420">File:Stage 13 MRI 3D02.mp4</html5media>

Week 4 - Stage 16

<html5media height="420" width="420">File:Stage 16 MRI 3D02.mp4</html5media>

Week 8 - Stage 23

<html5media height="500" width="540">File:Stage23 MRI S01.mp4</html5media>

The above MRI scan movie shows the structure of the central nervous system at the end of the embryonic period. Note the relative size and position of the CNS parts, the flexures, the size of the ventricular spaces and chord plexus within this space. There are additional Stage 23 movies available in the links below.

Week:	1	2	3	4	5	6	7	8
Carnegie stage:	1 2 3 4	5 6	7 8 9	10 11 12 13	14 15	16 17	18 19	20 21 22 23

Development Overview

Neuralation begins at the trilaminar embryo with formation of the notochord and somites, both of which underly the ectoderm and do not contribute to the nervous system, but are involved with patterning its initial formation. The central portion of the ectoderm then forms the neural plate that folds to form the neural tube, that will eventually form the entire central nervous system.

Early developmental sequence: Epiblast - Ectoderm - Neural Plate - Neural groove and Neural Crest - Neural Tube and Neural Crest

Neural Tube Development

Neural Tube	Primary Vesicles	Secondary Vesicles	Adult Structures
week 3	week 4	week 5	adult
neural plate neural groove neural tube Brain	prosencephalon (forebrain)	telencephalon	Rhinencephalon, Amygdala, hippocampus, cerebrum (cortex), hypothalamus‎, pituitary | Basal Ganglia, lateral ventricles
		diencephalon	epithalamus, thalamus, Subthalamus, pineal, posterior commissure, pretectum, third ventricle
	mesencephalon (midbrain)	mesencephalon	tectum, Cerebral peduncle, cerebral aqueduct, pons
	rhombencephalon (hindbrain)	metencephalon	cerebellum
		myelencephalon	medulla oblongata, isthmus
spinal cord, pyramidal decussation, central canal

Notochord

Does not contribute to the final nervous system, but is critical to patterning the development.

• forms initially as the Axial Process, a hollow tube which extends from the primitive pit , cranially to the oral membrane
• the axial process then allow transient communication between the amnion and the yolk sac through the neuroenteric canal.
• the axial process then merges with the Endodermal layer to form the Notochordal Plate.
• the notochordal plate then rises back into the Mesodermal layer as a solid column of cells which is the Notochord.

Links: Notochord

Ectoderm

Two main parts with different morphology

• columnar - midline neural plate forming neural tube and neural crest
• cuboidal - lateral surface ectoderm forming epidermis and sensory placodes
  • epidermis of skin, hair, glands, anterior pituitary, teeth enamel
  • sensory placodes

Links: Ectoderm

Neural Plate

The neural plate forms above the notochord and paraxial mesoderm and extends from the buccopharyngeal membrane to primitive node. The cells are described as neuroectodermal and form initially two regions along the head to tail axis: a cranial broad plate region (brain plate) and caudally a narrower plate region (spinal cord). Neural Determination Neuronal populations are thought to be specified before the plate folds by signals from underlying notochord and mesoderm, as well as signals spread laterally through the plate. secrete noggin, chordin, follistatin all factors bind BMP-4 an inhibitor of neuralation bone morphogenic protein acts through membrane receptor Lateral Inhibition generates at spinal cord level 3 strips of cells expression of delta inhibits nearby cells, which express notch receptor, from becoming neurons Delta-Notch- generates "neural strips"

‎‎Neural Plate Page | Play

Neural Bending

There are two bending processes occurring in the formation of the neural groove and neural tube.

1. occuring in the midline due to cells in this region having a basal nuclear localisation. This initial bending leads to formation of the neural groove.
2. occuring at the dorsolateral hinge points by different mechanism involving "buckling". This later bending leads to formation of the neural tube.

Mouse neural tube bending model (see review)

Neural Groove

In the human embryo the neural groove forms in the midline of the neural plate (day 18-19). either side of which are the neural folds continues to deepen until about week 4 neural folds begins to fuse at 4th somite level

Neural Groove human embryo (Carnegie stage 10, week 4)

Neural Tube

• fusion of neural groove extends rostrally and caudally
• begins at level of 4th somite, "zips up" neural groove
• leaves 2 openings at either end- Neuropores
• forms the brain and spinal cord
• Secondary Neuralation - caudal end of neural tube formed by secondary neuralation, develops from primitive streak region, solid cord canalized by extension of neural canal. mesodermal caudal eminence

Neuropores

Cranial Neuropore	Caudal Neuropore
(stage 11)	(stage 12)

• cranial (anterior) neuropore closes before caudal (posterior)
• failure to close - Neural Tube Defects (NTD), severity dependent upon level, spina bifida anancephaly (More? [neuron2.htm Neural Abnormalities])
• found that supplementation of maternal diet with folate reduces incidence of NTDs
  • A randomised controlled trial conducted by the Medical Research Council of the United Kingdom demonstrated a 72% reduction in risk of recurrence by periconceptional (ie before and after conception) folic acid supplementation (4mg daily).
  • Women who have one infant with a neural tube defect have a significantly increased risk of recurrence (40-50 per thousand compared with 2 per thousand for all births)

Lamina Terminalis

Note the site of the embryonic cranial neuropore can later be identified within the central nervous system as the lamina terminalis.

Human Fetus (week 10) brain showing lamina terminalis region

Neural Crest

• a population of cells at the edge of the neural plate that lie dorsally when the neural tube fuses
• dorsal to the neural tube, as a pair of streaks
• cells migrate throughout the embryo
• studied by quail-chick chimeras - transplanted quail cells have obvious nucleoli compared with chicken Neural Crest Derivitives

• pluripotential, forms many different types of cells: dorsal root ganglia (neurons, sheath cells, glia), autonomic ganglia, adrenal medulla, pia-arachnoid sheath, skin melanocytes, connective tissue of cardiac outflow, thyroid parafollicular cells, craniofacial skeleton and teeth odontoblasts.

Links: Neural Crest Development

Early Brain Structure

Primary Vesicles

• rostral neural tube forms 3 primary brain vesicles (week 4)
• 3 primary vesicles: prosencephalon (forebrain), mesencephalon (midbrain), rhombencephalon (hindbrain)

See also the week 4 embryo movie.

Secondary Vesicles

From the 3 primary vesicles developing to form 5 secondary vesicles (week 5)

• prosencephalon- telencephalon (endbrain, forms cerebral hemispheres), diencephalon (betweenbrain, forms optic outgrowth)
• mesencephalon
• rhombencephalon- metencephalon (behindbrain), myelencephalon (medullabrain)

See also the week 6 embryo movie.

Carnegie Stage 14 Secondary Vesicles (Week 5)
		Cranial Nerves  Nerve Number Name Type Origin Function CN I Olfactory sensory telencephalon smell placode CN II Optic sensory retinal ganglial cells vision CN III Oculomotor motor anterior midbrain extraocular muscles eye movements and pupil dilation (motor) CN IV Trochlear motor dorsal midbrain extraocular muscles (superior oblique muscle) CN V Trigeminal motor/sensory pons touch, mastication CN VI Abducent motor extraocular muscles control eye movements (lateral rectus muscle) CN VII Facial motor/sensory pons facial expression, taste (tongue anterior and central regions) regulate salivary production. CN VIII Acoustic sensory vestibular and cochlear nuclei hearing, placode CN IX Glossopharyngeal motor/sensory medulla swallowing and speech, taste (tongue posterior region) CN X Vagus motor/sensory medulla larynx and pharynx muscles (speech and swallowing), regulates heartbeat, sweating, and peristalsis CN XI Accessory motor motor neurons sternocleidomastoid and trapezius muscles CN XII Hypoglossal motor motor neurons tongue muscles (speech, eating and other oral functions)
Lateral view of the central nervous system of embryo at Carnegie stage 14 (Scale bar is 1 mm).

Week 8 - Stage 23

Ventricles

CNS ventricles

• cavity within tube will form the contiguious space of the ventricules of the brain and central canal of spinal cord
• this space is filled initially with amniotic fluid, later with CerebroSpinal Fluid (CSF)
• CSF is secreted by a modified vascular structure, the chorioid plexus, lying within the ventricles

Links: Neural - Ventricular System Development)

Brain Flexures

Rapid growth folds the neural tube forming 3 brain flexures (cranial to caudal)

• cephalic flexure - (mesencephalic) pushes mesencephalon upwards
• pontine flexure - (metencephalon) generates 4th ventricle
• cervical flexure - (myelencephalon) between brain stem and spinal cord

Neural Layers

Human Embryo (Week 8, Stage 22) developing head section

Stage 22 developing cortex

Neuron and supporting glial cells

• neural stem cells lie in the layer closest to the ventricular space, the ventricular layer
  • this layer generates both neuroblasts and glioblasts

Neuroblasts - neurons arise first as neuroblasts and migrate along radial gial, their migration stops at cortical plate. Glioblasts - glia arise later as glioblasts

Both neurons and glia undergo a complex process of growth, differentiation and interaction over a long developmental time period.

Spinal Cord Axes

• • Experimental manipulation of interactions.
  • Initial experiments looked at how isolated tissues may influence the development of the spinal cord.
  • Repositionining of specific tissues both in vivo and in vitro
  • specific markers of or alteration of differentiation.

Notocord Induction

• • Ventral- Sonic Hedgehog
  • notochord secretes sonic hedgehog
  • Gene expression studies (ISH) showed shh gene expression occured in a subset of inducing tissues
  • has a patterning role elsewhere (limb, sclerotome, lung)
  • 2 signaling activities acting (locally and at a distance) Ventral- Sonic Hedgehog
  • Binds to cell surface receptor patched
  • without shh, patched (Ptc) binds smoothened (Smo)
  • with shh shh-Ptc releases Smo activating G protein pathway

Early Development and Neural Derivatives

• bilaminar embryo- hyoblast
• trilaminar embryo then ectoderm layer, neural plate, neural groove, neural tube and neural crest
• cranial expansion of neural tube- central nervous system
• caudal remainder of neural tube- spinal cord
• neural crest
• dorsal root ganglia
• parasympathetic / sympathetic ganglia.
• ectodermal placodes- components of the special senses: otic placode (otocyst), nasal placode, lens placode

Links: Placodes

Neural tube and Genes: neural specification- Notch/Delta, patched receptor. Border- fibroblast growth factor (fgf), BMP (BMP4, msx1) Rostral border- Dlx5

Neural Tube Patterning

Review - Time for Radical Changes in Brain Stem Nomenclature-Applying the Lessons From Developmental Gene Patterns "The traditional subdivision of the brain stem into midbrain, pons, and medulla oblongata is based purely on the external appearance of the human brain stem. There is an urgent need to update the names of brain stem structures to be consistent with the discovery of rhomobomeric segmentation based on gene expression. The most important mistakes are the belief that the pons occupies the upper half of the hindbrain, the failure to recognize the isthmus as the first segment of the hindbrain, and the mistaken inclusion of diencephalic structures in the midbrain. The new nomenclature will apply to all mammals. This essay recommends a new brain stem nomenclature based on developmental gene expression, progeny analysis, and fate mapping."

Molecular Patterning Molecules

• segmented along its length - Hox/Lim gene expression
• ventral identity - sonic hedgehog, BMP7/chordin interaction
• dorsal identity - dorsalin

Fetal Development

Human Fetus (CRL 240mm) Brain (left dorsolateral view)

For more details see Neural System - Fetal

Fetal - Second Trimester

Brain and Ventricular Development	Brain Fissure Development

Third Trimester

Human Fetus (CRL 240mm) Brain

Three-dimensional magnetic resonance imaging and image-processing algorithms have been used to quantitate between 29-41 weeks volumes of: total brain, cerebral gray matter, unmyelinated white matter, myelinated, and cerebrospinal fluid (grey matter- mainly neuronal cell bodies; white matter- mainly neural processes and glia). A study of 78 premature and mature newborns showed that total brain tissue volume increased linearly over this period at a rate of 22 ml/week. Total grey matter also showed a linear increase in relative intracranial volume of approximately 1.4% or 15 ml/week. The rapid increase in total grey matter is mainly due to a fourfold increase in cortical grey matter. Quantification of extracerebral and intraventricular CSF was found to change only minimally.

Thyroid System and Neural Development

Human thyroid system and neural development

Timeline of human thyroid system and brain development from conception to birth. (Estimation of neurogenesis adapted from Bayer et al.)

Links: thyroid

Gliogenesis and Myelination

Glial cells have many different types and roles in central and peripheral neural development, though historically described as "supportive". (More? gliogenesis and myelination) These central glia develop from the same neural stem cells as neurons, while peripheral glia (Schwann cells) are derived from neural crest.

Early in neural development a special type of developmental glia, radial glia, provide pathway for developing neuron (neuroblasts) migration out from the proliferating ventricular layer and are involved in the subsequent lamination and columnar organization of the central nervous system.

Types of glia: radial glia, astroglia, oligodendroglia, microglia and Schwann cells.

Links: gliogenesis | Schwann cell

Gene Diseases - Sonic Hedgehog

SHH Human mutation- holoprosencephaly 3

• characteristic facies of the severe form of HPE which included a single fused eye (cyclopia) and a nose-like structure (proboscis) above the eye
• Downstream targets of Sonic hedgehog signalling: transcription factors like Gli3 (responsible for Greigs polycephalosyndactyly in humans), d Hoxd13 (responsible for polysyndactyly)

References

Journals

• Neural Development Browse contents
• Developmental Brain Research Content Listing
• Neural Development Welcome to Neural Development | Pubmed Central Volume 1 2006 | Pubmed Central Volume 2 2007 |
• International Journal for Developmental Neuroscience Official Journal of the International Society for Developmental Neuroscience |
• Developmental Neuroscience Journal Homepage | Hippocampal Development | Vol. 29, No. 3, 2007 |
• Neuroscience Official journal of The International Brain Research Organisation (IBRO)
• Neuron Neuroscience journal published by Cell press

Online Textbooks

Developmental Biology (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000. Formation of the Neural Tube | Differentiation of the Neural Tube | Tissue Architecture of the Central Nervous System | Neuronal Types | Snapshot Summary: Central Nervous System and Epidermis

Neuroscience Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc. ; c2001 Early Brain Development | Construction of Neural Circuits | Modification of Brain Circuits as a Result of Experience

Molecular Biology of the Cell (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002. Neural Development | The three phases of neural development

Health Services/Technology Assessment Text (HSTAT) Bethesda (MD): National Library of Medicine (US), 2003 Oct. Developmental Disorders Associated with Failure to Thrive

Search NLM Online Textbooks- "neural development" : Developmental Biology | The Cell- A molecular Approach | Molecular Biology of the Cell | Endocrinology

Reviews

Baker NE & Brown NL. (2018). All in the family: proneural bHLH genes and neuronal diversity. Development , 145, . PMID: 29720483 DOI.

Miranda A & Sousa N. (2018). Maternal hormonal milieu influence on fetal brain development. Brain Behav , 8, e00920. PMID: 29484271 DOI.

Nikolopoulou E, Galea GL, Rolo A, Greene ND & Copp AJ. (2017). Neural tube closure: cellular, molecular and biomechanical mechanisms. Development , 144, 552-566. PMID: 28196803 DOI.

Hardwick LJ, Ali FR, Azzarelli R & Philpott A. (2015). Cell cycle regulation of proliferation versus differentiation in the central nervous system. Cell Tissue Res. , 359, 187-200. PMID: 24859217 DOI.

Götz M & Huttner WB. (2005). The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. , 6, 777-88. PMID: 16314867 DOI.

Greene ND & Copp AJ. (2009). Development of the vertebrate central nervous system: formation of the neural tube. Prenat. Diagn. , 29, 303-11. PMID: 19206138 DOI.

Articles

Shinotsuka N, Yamaguchi Y, Nakazato K, Matsumoto Y, Mochizuki A & Miura M. (2018). Caspases and matrix metalloproteases facilitate collective behavior of non-neural ectoderm after hindbrain neuropore closure. BMC Dev. Biol. , 18, 17. PMID: 30064364 DOI.

Nikolopoulou E, Galea GL, Rolo A, Greene ND & Copp AJ. (2017). Neural tube closure: cellular, molecular and biomechanical mechanisms. Development , 144, 552-566. PMID: 28196803 DOI.

Yang HJ, Lee DH, Lee YJ, Chi JG, Lee JY, Phi JH, Kim SK, Cho BK & Wang KC. (2014). Secondary neurulation of human embryos: morphological changes and the expression of neuronal antigens. Childs Nerv Syst , 30, 73-82. PMID: 23760472 DOI.

Saitsu H & Shiota K. (2008). Involvement of the axially condensed tail bud mesenchyme in normal and abnormal human posterior neural tube development. Congenit Anom (Kyoto) , 48, 1-6. PMID: 18230116 DOI.

. (1970). Embryonic vertebrate central nervous system: revised terminology. The Boulder Committee. Anat. Rec. , 166, 257-61. PMID: 5414696 DOI.

Search PubMed

Search Pubmed: Neural System Development | Neural Development | Neural Tube Development | Spinal Cord Development

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Historic Disclaimer - information about historic embryology pages

Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Bartelmez GW. The subdivisions of the neural folds in man. (1923) J. Comp. Neural., 35: 231-247.

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  fig 1 Embryo no. 1878 Carnegie stage 9 Week 3.

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  fig 2 Embryo no. 3709 Carnegie stage 10 Week 4

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  fig 3 Eternod’s ‘DuGa’ embryo Carnegie stage 10 Week 4

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  fig 4 Veit and Esch embryo Carnegie stage 10 Week 4

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  fig 5 Carnegie Collection Embryo no. 1201a. Carnegie stage 11 Week 4

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  fig 6 Stages in the differentiation of the brain segments

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Terms

Neural Terms

Neural Development 3DMRI - Three-dimensional magnetic resonance imaging. A new technique that allows 3D analysis of embryonic structures. (More? Magnetic Resonance Imaging) 3rd ventricle - a fluid-filled space formed from neural tube lumen, located within the diencephalon (from the primary vesicle prosencephalon, forebrain). 4th ventricle - a fluid-filled space formed from neural tube lumen, located within the rhombencephalon (from the primary vesicle, hindbrain). adenohypophysis - (anterior pituitary) = 3 parts pars distalis, pars intermedia, pars tuberalis. afferent - refers to the direction of conduction from the periphery toward the central nervous system. Efferent is in the opposite direction. alar plate - embryonic dorsolateral region of the neural tube forming at spinal cord level dorsal horns (afferent) and brain level different structures. anlage - (German = primordium) structure or cells that will form a future adult structure. arachnoid mater - (G.) spider web-like used in reference to the middle layer of the brain meninges. astrocytes - cells named by their "star-like" branching appearance, are the most abundant glial cells in the brain, important for the blood-brain barrier. basal ganglia - (basal nuclei) neural structure derived from the secondary vesicle telencephalon (endbrain) structure from the earlier primary vesicle prosencephalon (forebrain). basal plate - embryonic ventrolateral region of the neural tube forming at spinal cord level ventral horns (efferent) and brain level different structures. brachial plexus - mixed spinal nerves innervating the upper limb form a complex meshwork (crossing). brain - general term for the central nervous system formed from 3 primary vesicles. buccopharyngeal membrane - (oral membrane) at cranial (mouth) end of gastrointestinal tract (GIT) where surface ectoderm and GIT endoderm meet. (see also cloacal membrane). cauda equina - (horse's tail) caudal extension of the mature spinal cord. central canal - lumen, cavity of neural tube within the spinal cord. Space is continuous with ventricular system of the brain. central cerebral sulcus - (central fissure, fissure of Rolando, Rolandic fissure) fold in the cerebral cortex associated with the sensorimotor cortex. cerebral aqueduct - ventricular cavity within the mesencephalon. cervical flexure - most caudal brain flexure (of 3) between spinal cord and rhompencephalon. choroid plexus - specialized vascular plexus responsible for secreting ventricular fluid that with further additions becomes cerebrospinal fluid (CSF). cloacal membrane - at caudal (anal) end of gastrointestinal tract (GIT) where surface ectoderm and GIT endoderm meet forms the openings for GIT, urinary, reproductive tracts. (see also buccopharyngeal membrane). connectome - term describing the detailed map of neural connections in the central nervous system. cortex - - CNS structure derived from the secondary vesicle telencephalon (endbrain) from the earlier primary vesicle prosencephalon (forebrain). cortical plate - outer neural tube region which post-mitotic neuroblasts migrate too along radial glia to form adult cortical layers. cranial flexure - (=midbrain flexure) most cranial brain flexure (of 3) between mesencephalon and prosencephalon. diencephalon - the caudal portion of forebrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). (cavity- 3rd ventricle) Forms the thalmus and other nuclei in the adult brain. (sc-My-Met-Mes-Di-Tel) dorsal root ganglia - (spinal ganglia) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord. dura mater- "tough" (Latin, mater = mother) used in reference to the tough outer layer of the brain meninges. ectoderm - the germ layer which form the nervous system from the neural tube, neural crest and placodes. efferent - refers to the direction of conduction from the central nervous system toward the periphery. Afferent is in the opposite direction. ependyma - epithelia of remnant cells after neurons and glia have been generated and left the ventricular zone. floorplate - early forming thin region of neural tube closest to the notochord. ganglia - (pl. of ganglion) specialized neural cluster within either the CNS or PNS. glia - supporting, non-neuronal cells of the nervous system. Generated from the same neuroepithelial stem cells that form neurons in ventricular zone of neural tube. Form astrocytes, oligodendrocytes. grey matter - neural regions containing cell bodies (somas) of neurons. In the brain it is the outer layer, in the spinal cord it is inner layer. (see white matter white matter). growth factor - usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg SHH). HOX - (homeobox) family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels. hydrocephalus - abnormality as the result of an imbalance between the rate at which the CSF is being formed and the rate at which the CSF is passing through the arachnoidal villi back into the blood (hydrocephalus rate is a function of the degree of imbalance in these two). Very small imbalance exhibit subtle, if any, symptoms. Large imbalances will have rapidly evolving symptoms of unmistakable import. isthmus- (G. narrow passage). lamina terminalis - anterior region of brain where cranial neuropore closes. lumbar plexus - mixed spinal nerves innervating the lower limb form a complex meshwork (crossing). mantle layer - layer of cells generated by first neuroblasts migrating from the ventricular zone of the neural tube. Layers are rearranged during development of the brain and spinal cord. (Ven-Man-Mar-CP) marginal zone - layer of processes from neuroblasts in mantle layer. (Ven-Man-Mar-CP) mater - (Latin, mater = mother) used in relation to the 3 layers of the meninges. meninges - mesenchyme surrounding neural tube forms 3 layer (Dura-, pia-, arachnoid- mater) connective tissue sheath of nervous system. (D-P-A-cns) mesencephalon - (midbrain), the middle portion of the 3 primary vesicle brain (week 4). (sc-R-M-P) metencephalon - the cranial portion of hindbrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). Forms the pons and cerebellum in the adult brain. (sc-My-Met-Mes-Di-Tel) microglia - CNS innate immune cells that have a macrophage function, derive from yolk sac progenitor cells migrating into the CNS. microglia myelencephalon - the caudal portion of hindbrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). Forms the medulla in the adult brain. (sc-My-Met-Mes-Di-Tel) neural tube - neural plate region of ectoderm pinched off to form hollow ectodermal tube above notochord in mesoderm. neural tube defect - (NTD) any developmental abnormality that affects neural tube development. Commonly failure of neural tube closure. neuroblast - undifferentiated neuron found in ventricular layer of neural tube. neurohypophysis - (posterior pituitary; pas nervosa) neuromere - (prosomere) the model units for segmental brain development regions based upon a series of neural tube transverse subunits. neuron - The cellur "unit" of the nervous system, transmitting signals between neurons and other cells. The post-mitotic cells generated from neuroepithelial stem cells (neuroblasts) in ventricular zone of neural tube. neuropore - opening at either end of neural tube cranial (rostral, anterior) neuropore closes (day 25) about 2 days before caudal (posterior) that closes at somite level 32 to 34. Neural Tube Defects (NTDs) can be due to failure of these two neuropores to close. notochord - rod of cells lying in mesoderm layer ventral to the neural tube, induces neural tube and secretes sonic hedgehog which "ventralizes" the neural tube. olfactory bulb - (cranial nerve I, CN I) bipolar neurons from nasal epithelium project axons through cribiform palate into olfactory bulb of the brain associated with smell. optic nerve - (cranial nerve II, CN II) retinal ganglion neurons project from the retina as a tract into the brain (at the level of the diencephalon) associated with vision. optic vesicle - diencephalon region of neural tube outgrowth that forms the primordia of the retina associated with vision. opercularization - during fetal development of the sensorimotor cortex, the insula (located deep within the lateral sulcus) begins to invaginate from the surface of the immature cerebrum, until at term, the opercula completely cover the insula. otocyst - (otic vesicle) sensory placode that sinks into mesoderm to form spherical vesicle (stage 13/14 embryo) that will form components of the inner ear associated with hearing. pars - (L. part of) pharyngeal arch - (branchial arch, Gk. gill) form the main structures of the head and neck. Humans have 5 arches appearing in week 4 that form 4 external swellings, each arch has a pouch, membrane and cleft. pharynx - uppermost end of GIT, beginning at the buccopharyngeal membrane and at the level of the pharyngeal arches. pia mater - (G.) (L. pius = soft, faithful + mater = mother) delicate vascular membrane which adheres to surface of brain and spinal cord, faithfully following their contours, the inner layer of the brain meninges. placode - specialized regions of ectoderm which form components of the sensory apparatus. pontine flexure - middle brain flexure (of 3) between cervical and cranial flexure in opposite direction, also generates thin roof of rhombencephalon and divides it into myelencephalon and metencephalon. ( sc-^V^ ) posterior insula - during sensorimotor cortex development this region is composed of the anterior and posterior long insular gyri and the postcentral insular sulcus, which separates them. prosencephalon - (forebrain), the most cranial portion of the 3 primary vesicle brain (week 4). (sc-R-M-P) prosomere - (neuromere) a model for segmental brain development based upon a series of neural tube transverse subunits. PMID 12948657 Rathke's pouch - a portion of the roof of the pharynx pushes upward towards the floor of the brain forming the anterior pituitary (adenohypophysis, pars distalis, pars tuberalis pars intermedia). Where it meets a portion of the brain pushing downward forming the posterior pituitary (neurohypophysis, pars nervosa). Rathke's pouch eventually looses its connection with the pharynx. rhombencephalon - (hindbrain), the most caudal portion of the 3 primary vesicle brain (week 4). (sc-R-M-P) rhombic lip - metencephalon posterior part extending from the roof of the fourth ventricle to dorsal neuroepithelial cells that contributes to the cerebellum. roofplate - early forming thin region of neural tube closest to the overlying ectoderm. spinal cord - caudal end of neural tube that does not contribute to brain. Note: the process of secondary neuralation contributes the caudal end of the spinal cord. spinal ganglia - (dorsal root ganglia, drg) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord. spinal nerve - mixed nerve (motor and sensory) arising as latera pairs at each vertebral segmental level. sonic hedgehog - (shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. sulcus - (L. furrow) groove. sulcus limitans - longitudinal lateral groove in neural tube approx. midway between roofplate and floorplate. Groove divides alar (dorsal) and basal (ventral) plate regions. sympathetic ganglia - telencephalon - the cranial portion of forebrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). (cavity- lateral ventricles and some of 3rd ventricle) Forms the cerebral hemispheres in the adult brain. (sc-My-Met-Mes-Di-Tel) thalamus - (G. thalamos= bedchamber) cns nucleus, lateral to 3rd ventricle, paired (pl thalami). thyroid hormone - hormone required for brain development. T3 (3,5,3′-triiodothyronine) binding to nuclear receptors then act as a transcription factor in both neurons and glial cells. iodine deficiency transcription factor - a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2) trigeminal ganglion - (cranial nerve V, CN V) first arch ganglion, very large and has 3 portions. vagal ganglion - (cranial nerve X, CN X) fourth and sixth arch ganglion, innervates the viscera and heart. ventricles - the fluid-filled interconnected cavity system with the brain. Fluid (cerebrospinal fluid, CSF) is generated by the specialized vascular network, the choroid plexus. The ventricles are directly connected to the spinal canal (within the spinal cord). ventricular zone - Neuroepithelial cell layer of neural tube closest to lumen. Neuroepithelial cells generate neurons, glia and ependymal cells. (Ven-Man-Mar-CP) vestibulocochlear nerve - (cranial nerve VIII, CN VIII, also called statoacoustic) white matter - - neural regions containing processes (axons) of neurons. In the brain it is the inner layer, in the spinal cord it is outer layer. (see grey matter).

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Cite this page: Hill, M.A. (2023, December 5) Embryology Neural System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Neural_System_Development

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G