UNSW Embryology

Neural Development - Fetal

© Dr Mark Hill (2008)

Acknowledgements

Introduction

General stages of brain development include: neural proliferation, neuroblast migration and neuronal differentiation.

(More? Neural Crest Notes | Senses Notes)

Page Links: Introduction | Some Recent Findings | Development Overview | Human Neuralation - Early Stages | Late Neural Development | Postnatal Neural | References | Glossary | Terms

Some Recent Findings

Pang T, Atefy R, Sheen V. Malformations of cortical development. Neurologist. 2008 May;14(3):181-91.

Neural Stem Cell Differentiation Goetz AK, Scheffler B, Chen HX, Wang S, Suslov O, Xiang H, Brustle O, Roper SN, Steindler DA. Temporally restricted substrate interactions direct fate and specification of neural precursors derived from embryonic stem cells. Proc Natl Acad Sci U S A. 2006 Jul 10; PNAS Link | Stem Cell Notes

"Upon evaluating distinct growth-permissive substrates in an embryonic stem cell–neurogenesis assay, we found that laminin, fibronectin, and gelatin instruct neural fate and alter the functional specification of neurons when applied at distinct stages of development."

Development Overview

Cortical maturation (sulcation and gyration) and vascularization of the lateral surface of the brain starts with the insular region.

Insular Gyral and Sulcal Development

13-17 gestational weeks - appearance of the first sulcus

18-19 gestational weeks - development of the periinsular sulci

20-22 gestational weeks - central sulci and opercularization of the insula

24-26 gestational weeks - covering of the posterior insula

27-28 gestational weeks - closure of the sylvian fissure

(Data from: Afif A, etal., 2007)

Second Trimester

(Clinical Week 14)

Week	Stage	Event
12	Clinical second trimester	Sense - Hearing – Week 12-16 - Capsule adjacent to membranous labrynth undegoes vacuolization to form a cavity (perilymphatic space) around membranous labrynth and fills with perilymph
13
14
15
16	14 cm	Sense - Hearing – Week 16-24 - Centres of ossification appear in remaining cartilage of otic capsule form petrous portion of temporal bone. Continues to ossify to form mastoid process of temporal bone. Pituitary – adenohypophysis fully differentiated
17
18
19
20		Pituitary – week 20 to 24 – growth hormone levels peak, then decline
21
22		Neural – brain cortical sulcation - sylvian fissure, interhemispheric fissure, callosal sulcus, parietooccipital fissure, and hippocampic fissures present (PMID:11158907)
23
24
25

Third Trimester

(Clinical Week 28)

Week	Stage	Event
`	Clinical third trimester	Sense - Hearing – 3rd Trimester - vibration acoustically of maternal abdominal wall induces startle respone in fetus.
27
28
29
30
31
32
33		Neural – brain cortical sulcation - primary sulci present (PMID:11158907)
34		Neural – brain cortical sulcation - insular, cingular, and occipital secondary sulci present (PMID:11158907)
35
36
37
38	Birth	Clinical Week 40 Heart – pressure difference closes foramen ovale leaving a fossa ovalis Thyroid – TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels Adrenal - zona glomerulosa, zona fasiculata present

Postnatal

Week	Stage	Event
+1
+2
+3
+4
+5
Year
Year1
Year 2
Year 3		Adrenal - Year 3 – zona reticularis present
4
5
37
38

Human Neuralation - Early Stages

The stages below refer to specific Carneigie stages of development.

• stage 8 (about 18 postovulatory days) neural groove and folds are first seen
• stage 9 the three main divisions of the brain, which are not cerebral vesicles, can be distinguished while the neural groove is still completely open.
• stage 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
• stage 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.
• stage 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
• stage 13 (4 weeks) the neural tube is normally completely closed
• Secondary neurulation begins at stage 12
  • 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.

(Text modified from: Neurulation in the normal human embryo. O'Rahilly R, Muller F Ciba Found Symp 1994;181:70-82)

Late Neural Development

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. (text modified from Huppi etal., (1998) Quantitative magnetic resonance imaging of brain development in premature and mature newborns.Ann Neurol 43(2):224-235.) (More? Late Neural Development)

Postnatal Neural

Neural development continues after birth with substantial growth, death and reorganization occuring during the postnatally. (More? Postnatal Development - Neural) The references below give a sample of some recent findings and research methods.

Cortex Matures Faster in Youth with Highest IQ (More? NIH - Cortex Matures Faster in Youth with Highest IQ)

Stern CD. Neural induction: old problem, new findings, yet more questions. Development. 2005 May;132(9):2007-21. Review. "During neural induction, the embryonic neural plate is specified and set aside from other parts of the ectoderm. A popular molecular explanation is the 'default model' of neural induction, which proposes that ectodermal cells give rise to neural plate if they receive no signals at all, while BMP activity directs them to become epidermis. However, neural induction now appears to be more complex than once thought, and can no longer be fully explained by the default model alone. This review summarizes neural induction events in different species and highlights some unanswered questions about this important developmental process."

Snook L, Paulson LA, Roy D, Phillips L, Beaulieu C. Diffusion tensor imaging of neurodevelopment in children and young adults. Neuroimage. 2005 Jul 15;26(4):1164-73. "Diffusion tensor magnetic resonance imaging (DTI) was used to study regional changes in the brain's development from childhood (8-12 years, mean 11.1 +/- 1.3, N = 32) to young adulthood (21-27 years, mean 24.4 +/- 1.8, N = 28). ..... These findings suggest a continuation of the brain's microstructural development through adolescence."

Abnormal

References

Many of the links below are to external resources and require an internet connection.

Links: Earlier References | Journals | Online Textbooks | Search Textbooks | PubMed | Search PubMed | Books | Glossary

1999 and Earlier References: Neuralation | Notch Articles/Reviews | Sonic Hedgehog Articles/Reviews | Dorsal | Clinical | Folate |

Journals

Glia Content Listing

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. The three phases of neural development |

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

PubMed

Reviews

Prayer D, Brugger PC. Investigation of normal organ development with fetal MRI. Eur Radiol. 2007 Oct;17(10):2458-71.

Casanova MF, Trippe J 2nd. Regulatory mechanisms of cortical laminar development. Brain Res Rev. 2006 Jun;51(1):72-84.

Naidich TP, Grant JL, Altman N, Zimmerman RA, Birchansky SB, Braffman B, Daniel JL. The developing cerebral surface. Preliminary report on the patterns of sulcal and gyral maturation--anatomy, ultrasound, and magnetic resonance imaging. Neuroimaging Clin N Am. 1994 May;4(2):201-40.

Articles

Pang T, Atefy R, Sheen V. Malformations of cortical development. Neurologist. 2008 May;14(3):181-91.

Afif A, Bouvier R, Buenerd A, Trouillas J, Mertens P. Development of the human fetal insular cortex: study of the gyration from 13 to 28 gestational weeks. Brain Struct Funct. 2007 Dec;212(3-4):335-46.

Bendersky M, Musolino PL, Rugilo C, Schuster G, Sica RE. Normal anatomy of the developing fetal brain. Ex vivo anatomical-magnetic resonance imaging correlation. J Neurol Sci. 2006 Dec 1;250(1-2):20-6.

Books

Note: books are listed for educational and information purposes only and does not suggest a commercial product endorsement.

Molecular and Cellular Approaches to Neural Development

The Embryonic Human Brain: An Atlas Of Developmental Stages, 3rd Edition

Modeling Neural Development

The Female Brain

Search PubMed

Search Jun2008 "fetal brain development" ?? reference articles of which ?? were reviews.

Search PubMed: term= fetal brain development | gyration | sulcation

Glossary of Terms

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z

Neural Development Terms

Only brief descriptions are given below, more complete definitions can be found in the glossary.

• 3DMRI Three-dimensional magnetic resonance imaging. A new technique that allows 3D analysis of embryonic structures. (More? Prenatal Diagnosis - Magnetic Resonance Imaging)
• 3rd ventricle ventricular cavity within the diencephalon.
• 4th ventricle ventricular cavity within the rhombencephalon.
• accessory nerve-
• adenohypophysis anterior pituitary= 3 parts pars distalis, pars intermedia, pars tuberalis
• alar plate afferent, dorsal horns
• anlage (German = primordium, structure or cells which will form a future structure.
• arachnoid- (G.) spider web-like
• basal ganglia-
• basal plate efferent, ventral horns
• 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.
• cerebral aqueduct ventricular cavity within the mesencephalon.
• cervical flexure most caudal brain flexure (of 3) between spinal cord and rhompencephalon.
  • ( sc-^V^ )
• 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)
• cortex-
• 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.
  • ( sc-^V^ )
• 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-
• ectoderm the germ layer which form the nervous system from the neural tube and neural crest.
• 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.
• glia supporting, non-neuronal cells of the nervous system. Generated from neuroepithelial stem cells in ventricular zone of neural tube. Form astrocytes, oligodendrocytes.
• glossopharyngeal ganglion-
• 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)
• 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.
• intervertebral foramina-
• isthmus- (G. narrow passage)
• lamina terminalis anterior region of brain where cranial neuropore closes.
• lissencephaly smooth brain, developmental brain abnormality resulting from an absence (agyria) or the paucity (pachygyria) of cerebral convolutions.
• 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 (L. mother)
• 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)
• 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)
• 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, caudal=posterior. The cranial neuropore closes (day 25) approx. 2 days (human) before caudal.
• 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.
• optic cup-
• 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).
• otocyst (=otic vesicle) sensory placode which sinks into mesoderm to form spherical vesicle (stage 13/14 embryo) that will form components of the inner ear.
• pars (L. part of)
• pharyngeal arches (=branchial arches, Gk. gill) form structures of the head. Six arches form but only 4 form any structures. 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-
• 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^ )
• prosencephalon (=forebrain), the most cranial portion of the 3 primary vesicle brain (week 4).
  • (sc-R-M-P)
• Rathke's pouch a portion of the roof of the pharynx pushes upward towards the floor of the brain forming the anterior pituirary (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. (Martin Heinrich Rathke 1973-1860, embryologist and anatomist)
• rhombencephalon (=hindbrain), the most caudal portion of the 3 primary vesicle brain (week 4).
  • (sc-R-M-P)
• 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).
• 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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