UNSW Embryology

Neural System Molecular Development

© Dr Mark Hill (2011)

Acknowledgements

Introduction

In the early trilaminar embryo how does a region of simple epithelium (which will also form the skin) become molecularly segregated, patterned, folded, proliferate, pattern again, proliferate, form layers and connections and also selectively die? Neural molecular development is one of the earliest to begin and the last to be complete, generating the most complex structure within the embryo.

Sonic Hedgehog (white) expression in both the notocord (pale circular) and neural tube floorplate (bright triangle). (Image - Lance Davidson)

For more specific details also look in Molecular Development sections on Sonic Hedgehog, Hox genes, Axis formation and Neural Axis patterning. Molecular neural crest development is also covered elsewhere. (More? Notes- Neural Crest)

Page Links: Introduction | Some Recent Findings | Neural Stem Cells | Neural Plate/Tube | Spinal Cord | Brain | Human Neuralation | Development Overview | Terms | References | Glossary

Some Recent Findings

Kondo T, Sheets PL, Zopf DA, Aloor HL, Cummins TR, Chan RJ, Hashino E. Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells.
Proc Natl Acad Sci U S A. 2008 Apr 7

"The T cell leukemia 3 (Tlx3) gene has been implicated in specification of glutamatergic sensory neurons in the spinal cord. ...The sequential and coordinated expression of the proneural and neuronal subtype-specific genes identifies Tlx3 as a selector gene in ES cells undergoing neural differentiation."

Transcriptional Regulation of spinal cord differentiation - a recent paper has analysed the transcription factors (proteins that bind DNA and activate/repress protein expression) that are active during development of the spinal cord Kioussi C, Shih HP, Loflin J, Gross MK. Prediction of active nodes in the transcriptional network of neural tube patterning. Proc Natl Acad Sci U S A. 2006 Nov 28

"Microarray comparisons across the partition led to an estimate of 500–700 active sequence-specific DNA-binding transcription factors (SSTFs) nodes in the transcriptional network of the developing NT. These included most of the 66 known SSTFs assembled from review articles and recent reports on NT patterning."

(More? Spinal Cord)

Neural Stem Cell Differentiation

"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." 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; [Epub ahead of print] PNAS Link | Stem Cell Notes

Neural Stem Cells

Kondo T, Sheets PL, Zopf DA, Aloor HL, Cummins TR, Chan RJ, Hashino E. Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells.
Proc Natl Acad Sci U S A. 2008 Apr 7

"The T cell leukemia 3 (Tlx3) gene has been implicated in specification of glutamatergic sensory neurons in the spinal cord. ...The sequential and coordinated expression of the proneural and neuronal subtype-specific genes identifies Tlx3 as a selector gene in ES cells undergoing neural differentiation."

(More? Factors - Tlx | Stem Cell Notes)

Neural Plate/Tube

Neural Determination- Neural Plate neuronal populations are specified before plate folds; signals from notochord and mesoderm secrete noggin, chordin, follistatin. All factors bind bone morphogenic protein 4 (BMP-4) an inhibitor of neuralation which acts through membrane receptor.

Neural Determination- Neural populations neuronal populations are also specified before plate fold lateral inhibition generates at spinal cord level 3 strips of cells. Expression of delta inhibits nearby cells, which express notch receptor, from becoming neurons generates neural strips.

Neural tube and Genes

neural specification - Notch/Delta, patched receptor

border- fibroblast growth factor (fgf), BMP (BMP4, msx1)

rostral border- Dlx5

Cornell RA, Ohlen TV Vnd/nkx, ind/gsh, and msh/msx: conserved regulators of dorsoventral neural patterning? Curr Opin Neurobiol 2000 Feb;10(1):63-71. "Expression of vnd in ventral, ind in intermediate, and msh in dorsal columns of fly neurectoderm, and of homologous gene families in corresponding domains of vertebrate neurectoderm, suggests that elements of dorsoventral neural patterning have been evolutionarily conserved. However, upstream signaling pathways regulating this columnar gene expression pattern appear to have diverged significantly throughout evolution. In addition, while recent loss-of-function studies in flies and mice indicate that these three genes may have a conserved role in regional specification, there is no obvious conservation of the particular cell fates deriving from corresponding domains. The three-column expression pattern may thus represent a developmental mechanism that is more resistant to evolutionary changes than genetic events upstream or downstream of it."

Spinal Cord

Transcriptional Regulation of spinal cord differentiation - a recent paper has analysed the transcription factors (proteins that bind DNA and activate/repress protein expression) that are active during development of the spinal cord Kioussi C, Shih HP, Loflin J, Gross MK. Prediction of active nodes in the transcriptional network of neural tube patterning. Proc Natl Acad Sci U S A. 2006 Nov 28 "Microarray comparisons across the partition led to an estimate of 500–700 active sequence-specific DNA-binding transcription factors (SSTFs) nodes in the transcriptional network of the developing NT. These included most of the 66 known SSTFs assembled from review articles and recent reports on NT patterning."

"Known active nodes included those that were expressed at higher (Lbx1, Pax2, Lmx1b, and Zic1), lower (Isl1, Foxd3, and Olig3), or similar (Zic2, Zic4, and Zic5) levels in green pools. Newly predicted active nodes also included those that were measured at higher (Mafa, Sall4, Bcl11a, Bcl11b Gbx2, Pknox2, Satb2, Uncx4.1, Tsh2, and Pax8) or lower (Nr4a2, Sall1, Hmx2, Hmx3, Otp, and FoxP2) levels in green cells."

Spinal Cord Axes

Ventral

• 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

Gene Diseases

• 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

Dorsal

• Dorsalin, growth factor controls patterning in embryonic mesoderm (frog)
• Transforming Growth factor beta, (TGF b)
  • related factors BMP-2, BMP-4, BMP-7, radar
  • flies related protein determines dorsoventral
• homology search of vertebrate library identified protein of same family.
• dorsalin-1 (dsl-1)
  • Basler, Cell 73, p687, 1993

Dorsalin-1

• From overlying ectoderm
• Naming comes from the obvious reason that it promotes the differentiation of neural crest cells.
• Also signal for dorsal signal of neural tube.
• Inhibits the differentiation of motoneurons.
• Implication is that dsl-1 and shh act antagonistically, or competitively to establish d-v axis of neural tube.

Rostro-Caudal Axis

• What about the third pattern axis?
• Brain rostro-caudal axis is generated by differential expression of Hox genes.
• Transcriptional activators.
  • corresponding to genetic order on chromosome.
  • Wilkinson, Nature, 341, p405, 1989

Brain

Rhombomeres

The vertebrate hindbrain transiently subdivides into a series of compartments called rhombomeres. Genes have been identified whose expression patterns distinguish these cellular compartments. Two of these genes, Hoxa1 and Hoxa2, have been shown to be required for proper patterning of the early mouse hindbrain and the associated neural crest. Critical to the model is the demonstration that Hoxa1 activity is required to set the anterior limit of Hoxb1 expression at the presumptive r3/4 rhombomere boundary. Failure to express Hoxb1 to this boundary in Hoxa1 mutant embryos initiates a cascade of gene misexpressions that result in misspecification of the hindbrain compartments from r2 through r5. Subsequent to misspecification of the hindbrain compartments, ectopic induction of apoptosis (from Barrow et al., 2000) (More? Hox genes)

Hox Genes

• Stands for Homeobox domain Genes
• A family of transcription factors
• Discovered in flies and conserved between all species. antennapedia
• Expressed in sequence along the embryo rostro-caudal axis.
• Regulate many other aspects of development.
• 180aa region binds DNA and regulate gene expression
• large family of genes organized and expressed in sequence on the chromosome
• Nkx-2.2 first detected at 1 somite stage
• Lim hox gene expressed at spinal cord level

Human Neuralation

Carnegie Stages

• 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, occuring at multiple sites
  • 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.

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

Development Overview

Human Neuralation | Neural Derivatives | Neural Genes | Neural Patterning

• Trilaminar Embryo
  • Neuralation begins at the trilaminar embryo with formation of the Notochord and somites, which underly the Ectoderm and do not contribute to the nervous system, but are involved with patterning its initial formation.
• Notochord
  • 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.
• Ectoderm
  • 2 parts
  • midline neural plate
    • columnar
  • lateral surface ectoderm
    • cuboidal
    • sensory placodes
    • epidermis of skin, hair, glands, ant. pituitary, teeth enamel
• Neural Plate
  • extends from buccopharyngeal membrane to primitive node
  • forms above notochord and paraxial mesoderm
  • neuroectodermal cells
    • broad brain plate
    • narrower spinal cord
  • 3 components form
    • floor plate
    • neural plate
    • neural crest
• 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 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 closes before caudal
  • failure to close- Neural Tube Defects
  • severity dependent upon level
    • spina bifida

• Neural Crest (More? for more detailed information see Notes- 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
  • pluripotential
    • forms many different types of cells
  • cells migrate throughout the embryo
  • studied by quail-chick chimeras
  • transplanted quail cells have obvious nucleoli compared with chicken
  • Neural Crest Derivitives
    • dorsal root ganglia
    • autonomic ganglia
    • adrenal medulla
    • drg sheath cells, glia
    • pia-arachnoid sheath
    • skin melanocytes
    • connective tissue of cardiac outflow
    • thyroid parafollicular cells
    • craniofacial skeleton
    • teeth odontoblasts
• Early Brain Structure- 3 primary vesicles
  • rostral neural tube forms 3 primary brain vesicles (week 4)
  • prosencephalon (forebrain)
  • mesencephalon (midbrain)
  • rhombencephalon (hindbrain)
• Early Brain Structure- 5 secondary vesicles
  • from the 3 vesicle 5 secondary vesicles form
    • prosencephalon
      • telencephalon (endbrain, forms cerebral hemispheres)
      • diencephalon (betweenbrain, forms optic outgrowth)
    • mesencephalon
    • rhombencephalon
      • metencephalon (behindbrain)
      • myelencephalon (medullabrain)
• Ventricles (More? for more detailed information see Notes- Chorioid Plexus)
  • 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
• Brain Flexures
  • rapid growth folds the neural tube forming 3 flexures
  • Brain Flexures
    • cervical flexure
      • between brain stem and spinal cord
    • midbrain flexure
      • pushes mesencephalon upwards
    • pontine flexure
      • generates 4th ventricle
• Neural Layers
  • neural stem cells lie in the layer closest to the ventricular space, the ventricular layer
  • this layer generates both neuroblasts and glioblasts
  • neuroblasts arise first and migrate along radial gial
  • their migration stops at cortical plate

 

Early Development and Neural Derivatives

• bilaminar embryo- hyoblast
• trilaminar embryo
  • 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

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 | Numbers | Old Glossary

Neural Development Terms

• 3DMRI- Three-dimensional magnetic resonance imaging. A new technique that allows 3D analysis of embryonic structures.
• 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- (Ger. ) 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.
• 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)

References

Selected Lists of References from PubMed March 1999 search results are available for Department of Anatomy computers without internet access. Computers with internet access can search from either Page 2 or PubMed Internet Access | Selected Research Articles and Reviews

Neuralation Articles/Reviews (1999)

• Bronner-Fraser M, et al. [See Related Articles] Differentiation of the vertebrate neural tube. Curr Opin Cell Biol. 1997 Dec;9(6):885-91. Review.
• Sasai Y, et al. [See Related Articles] Ectodermal patterning in vertebrate embryos. Dev Biol. 1997 Feb 1;182(1):5-20. Review.
• Scotting PJ, et al. [See Related Articles] Transcription factors in early development of the central nervous system. Neuropathol Appl Neurobiol. 1996 Dec;22(6):469-81. Review.
• Bartlett PF, et al. [See Related Articles] Regulation of neural stem cell differentiation in the forebrain. Immunol Cell Biol. 1998 Oct;76(5):414-8.
• McMahon JA, et al. [See Related Articles] Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 1998 May 15;12(10):1438-52.
• Pabst O, et al. [See Related Articles] Nkx2-9 is a novel homeobox transcription factor which demarcates ventral domains in the developing mouse CNS. Mech Dev. 1998 Apr;73(1):85-93.
• Ericson J, et al. [See Related Articles] Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell. 1997 Jul 11;90(1):169-80.
• Hynes M, et al. [See Related Articles] Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron. 1997 Jul;19(1):15-26.
• Shimamura K, et al. [See Related Articles] Inductive interactions direct early regionalization of the mouse forebrain. Development. 1997 Jul;124(14):2709-18.

Recent Notch Articles/Reviews

• Artavanis-Tsakonas S, et al. [See Related Articles] Notch signaling: cell fate control and signal integration in development. Science. 1999 Apr 30;284(5415):770-6. Review.
• Lanford PJ, et al. [See Related Articles] Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet. 1999 Mar;21(3):289-92.
• Gray GE, et al. [See Related Articles] Human ligands of the Notch receptor. Am J Pathol. 1999 Mar;154(3):785-94.
• Joutel A, et al. [See Related Articles] Notch signalling pathway and human diseases. Semin Cell Dev Biol. 1998 Dec;9(6):619-25. Review.
• Panin VM, et al. [See Related Articles] Modulators of Notch signaling. Semin Cell Dev Biol. 1998 Dec;9(6):609-17. Review.
• Jarriault S, et al. [See Related Articles] Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol. 1998 Dec;18(12):7423-31.
• Struhl G, et al. [See Related Articles] Nuclear access and action of notch in vivo. Cell. 1998 May 15;93(4):649-60.
• Matsuno K, et al. [See Related Articles] Human deltex is a conserved regulator of Notch signalling. Nat Genet. 1998 May;19(1):74-8.
• Kimble J, et al. [See Related Articles] The LIN-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol. 1997;13:333-61. Review.
• Kunisch M, et al. [See Related Articles] Lateral inhibition mediated by the Drosophila neurogenic gene delta is enhanced by proneural proteins. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10139-43.

Recent Sonic Hedgehog Articles/Reviews

• Briscoe J, et al. [See Related Articles] The specification of neuronal identity by graded sonic hedgehog signalling. Semin Cell Dev Biol. 1999 Jun;10(3):353-62.
• Odent S, et al. [See Related Articles] Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum Mol Genet. 1999 Sep;8(9):1683-1689.
• Lee J, et al. [See Related Articles] Gli1 is a target of Sonic hedgehog that induces ventral neural tube development.
  Development. 1997 Jul;124(13):2537-52.
• Sasaki H, et al. [See Related Articles] Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development. 1999;126(17):3915-3924.
• Meyers EN, et al. [See Related Articles] Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science. 1999 Jul 16;285(5426):403-6.
• Pierani A, et al. [See Related Articles] A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord. Cell. 1999 Jun 25;97(7):903-15.
• Goodrich LV, et al. [See Related Articles] Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube. Dev Biol. 1999 Jul 15;211(2):323-34.
• Dahmane N, et al. [See Related Articles] Sonic hedgehog regulates the growth and patterning of the cerebellum. Development. 1999 Jun;126(14):3089-100.
• Miao N, et al. [See Related Articles] Sonic hedgehog promotes the survival of specific CNS neuron populations and protects these cells from toxic insult In vitro. J Neurosci. 1997 Aug 1;17(15):5891-9.
• Chang BE, et al. [See Related Articles] Axial (HNF3beta) and retinoic acid receptors are regulators of the zebrafish sonic hedgehog promoter. EMBO J. 1997 Jul 1;16(13):3955-64.
• Levin M. [See Related Articles] Left-right asymmetry in vertebrate embryogenesis. Bioessays. 1997 Apr;19(4):287-96. Review.
• Bruneau S, et al. [See Related Articles] Dynamo, a new zebrafish DVR member of the TGF-beta superfamily is expressed in the posterior neural tube and is up-regulated by Sonic hedgehog. Mech Dev. 1997 Jan;61(1-2):199-212.
• Marigo V, et al. [See Related Articles] Biochemical evidence that patched is the Hedgehog receptor. Nature. 1996 Nov 14;384(6605):176-9.
• Marigo V, et al. [See Related Articles] Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9346-51.
• Roessler E, et al. [See Related Articles] Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996 Nov;14(3):357-60.

Recent Dorsal Articles

• Basler K, et al. [See Related Articles] Control of cell pattern in the neural tube: regulation of cell differentiation by dorsalin-1, a novel TGF beta family member. Cell. 1993 May 21;73(4):687-702.

Recent Clinical Articles

•  Kalucy M, et al. [See Related Articles] School-aged children with spina bifida in Western Australia--parental perspectives on functional outcome. Dev Med Child Neurol. 1996 Apr;38(4):325-34.
• McComb JG. [See Related Articles] Spinal and cranial neural tube defects. Semin Pediatr Neurol. 1997 Sep;4(3):156-66. Review.
• Bahado-Singh RO, et al. [See Related Articles] New triple screen test for Down syndrome: combined urine analytes and serum AFP. J Matern Fetal Med. 1998 May-Jun;7(3):111-4.
• Palka G, et al. [See Related Articles] Prenatal diagnosis using the triple test. Minerva Ginecol. 1998 Oct;50(10):411-5.
• Kinlaw K. [See Related Articles] The changing nature of neonatal ethics in practice. Clin Perinatol. 1996 Sep;23(3):417-28. Review.
• Ming JE, et al. [See Related Articles] Holoprosencephaly: from Homer to Hedgehog. Clin Genet. 1998 Mar;53(3):155-63. Review.
• Copp AJ, et al. [See Related Articles] The embryonic development of mammalian neural tube defects.
  Prog Neurobiol. 1990;35(5):363-403. Review. No abstract available.
• Copp AJ. [See Related Articles] Neural tube defects. Trends Neurosci. 1993 Oct;16(10):381-3. Review.

Recent Folate Articles

• Gonzalez MJ, et al. [See Related Articles] Folate supplementation and neural tube defects: a review of a public health issue. P R Health Sci J. 1997 Dec;16(4):387-93. Review.

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