Vertebrate Central Nervous System: Pattern Formation

Abstract

Deciphering the genetic instructions used by the embryo to establish the spatial order of its neuronal populations and their interconnections is the key to understand the wonderfully complex structure of the adult brain and spinal cord. The vertebrate central nervous system develops from a single ‘plate’ of ectoderm cells that fold into the neural tube. Localized signalling centres are placed at defined positions both outside and within the neural plate and tube, and trigger the differentiation of nerve cells. The centres secrete and combine a variety of morphogens that determine, in time and space, the repertoire of genes expressed by neurons in different regions of the nervous system. Gradients and countergradients of morphogens act along the three principal axes – antero‐posterior, dorso‐ventral and left–right – to regulate and coordinate the appearance of diverse neuronal subtypes in their correct anatomical locations.

Key Concepts:

  • The central nervous system develops from an epithelial ‘plate’ of ectoderm cells, triggered by molecular signals from the early midline mesoderm (‘neural induction’).

  • Several localized signalling centres, placed both outside and within the neural tube, coordinate patterning and regional differentiation of the nervous system.

  • The centres establish gradients and countergradients of a variety of morphogens that generate a patterned array of different nerve cell types.

  • Morphogen gradients generate discrete changes in the populations of transcription factors expressed by individual cells.

  • Morphogens have different effects according to the differentiation state of the cells they influence.

  • Diversity in the nervous system arises from the action of a small set of morphogen families expressed in the right place at the right time, such as: SHH, retinoic acid, Wnts, BMPs/TGFβs and FGFs.

Keywords: forebrain patterning; hindbrain patterning; midbrain–hindbrain boundary; neural induction; segmentation; spinal cord patterning

Figure 1.

Neurulation and the formation of major morphological subdivisions of the central nervous system. (a) Formation of the neural tube from the neural plate (neurulation), shown in sections transverse to the neuraxis as development proceeds. Prospective neural crest cells (green) lie at the margin of the neural plate, between neuroectoderm and surface ectoderm (blue). The neural crest‐containing regions (neural folds) elevate and fuse at the dorsal midline, leading to ectodermal continuity over the dorsal surface of the embryo and the dispersal of crest cells within the mesodermal domain. One consequence of tube formation is that the median, most dorsal, region of the neural plate becomes translated into the most ventral region of the neural tube (floor plate; orange). The middorsal mesoderm (notochord) is also shown (orange). (b) Stages in subdivision of the neural tube in the chick embryo. Early fate restriction at the closing neural tube stage (7) anticipates later morphological regions. At stage 9, the brain has three vesicles: forebrain (prosencephalon, P), midbrain (mesencephalon, M) and hindbrain (rhombencephalon, R). Later, the forebrain subdivides into telencephalon (T) and diencephalon (D), whereas the rhombencephalon is partitioned into eight segments (rhombomeres, r1–r8). There is no sharp morphological distinction between hindbrain and spinal cord (SC). By stage 12, placodes (localized thickenings of the neural ectoderm) for the cranial ganglia (trigeminal (gV) and facial or vestibuloacoustic (gVII/VIII) nerves) are evident. Reproduced from Cowan WM, Jessell TM and Zipursky SL (eds) (1997) Molecular and Cellular Approaches to Neural Development. Oxford: Oxford University Press. Used by permission of Oxford University Press.

Figure 2.

Gastrulation and neural induction in Xenopus. (a) Series of stages, seen at the median plane of the embryo. At the late blastula stage (top), the presumptive mesoderm (red) and endoderm (orange) form the marginal zone around the equator, and the future nervous system (green) forms the dorsal sector of the anterior (animal pole) ectoderm, the remainder of which (blue) forms epidermis. Gastrulation begins with the invagination of specialized cells at the blastopore, followed by the involution of marginal zone cells over the dorsal lip of the blastopore. The ectoderm spreads ventrally towards the posterior (vegetal) pole by epiboly whereas the mesoderm and endoderm that forms the archenteron roof converge on the dorsal midline and extend on the anteroposterior (AP) axis. The region of involution spreads from the dorsal lip posteriorly until it encircles the last remaining vegetal pole cells. Endoderm cells lie beneath the anterior end of the induced neural plate. In the two‐step model of neural induction, initial activation or neuralization involves both vertical (arrowheads) and planar (arrows) signalling from dorsal blastopore lip and involved endomesoderm. This is followed by transformation of the induced neurectoderm to a progressively more posterior character by a gradient of fibroblast growth factor or retinoic acid. The AP extent of the central nervous system, and therefore the distances over which posteriorizing signals are required to act, is extremely short at the start of gastrulation. Subsequently the neuraxis becomes elongated by the convergence–extension movements of gastrulation. (b) The organizer experiment of Mangold and Spemann (performed in the newt Triturus). The blastopore lip (red) of a donor embryo grafted to the ventral marginal region of a host embryo results in a twin embryonic axis being formed from ventral cells. The graft itself makes only a minor contribution to the secondary axis, the remainder of which is induced from the host. The nervous system of the secondary axis arises from cells whose normal fate would have been to form epidermis. Note that the secondary axis has the same orientation and polarity as the primary axis; it now appears that this is because anteroposterior polarity is established in the entire ectoderm before neural induction. (After Ruiz I and Ataba A (1998) Neural patterning: deconstructing the organizer. Nature391: 748–749.) (c) The neural default model. The ectoderm of Xenopus contains soluble molecules such as bone morphogenetic proteins (BMPs) that inhibit neural differentiation and promote epidermal differentiation when binding their receptors. Neural induction is thought to occur by the secretion from the organizer of molecules such as chordin, noggin and follistatin that bind and inactivate the neural inhibitory BMPs, preventing epidermal induction. The default state of the entire ectoderm is thus neural rather than, as was previously thought, epidermal. Reprinted from Weinstein DC and Hemmati‐Brivanlou A (1997) Neural induction in Xenopus laevis: evidence for the default model. Current Opinion in Neurobiology7: 7–12. Copyright © 1997, with permission from Elsevier Science.

Figure 3.

Distinct activities during neural induction. Anterior of embryo to the top. (a) Neuralizing signals emanating from the axial/midline endomesoderm (notochord and prechordal endomesoderm) inhibit neural inhibitors in the overlying ectoderm. (b) Posteriorizing signals from later involuting cells or from the node induce a progressively more posterior specification state in the neurectoderm. (c) At the anterior pole a secondary signalling centre influences forebrain development.

Figure 4.

(a) At the early neural tube stage, the anteroposterior (AP) axis of the central nervous system is already subdivided into prospective regions with different potentials. A secondary signalling centre operates at the isthmus (blue) refining local AP pattern in midbrain (M) and anterior hindbrain (H). Sonic hedgehog (SHH) is expressed in the notochord (n; red) and prechordal mesoderm (pcp; orange) and also in the floor plate at the ventral midline of the tube (red). SHH expression in the ventral structures influences cell pattern in adjacent regions of the neural tube (red arrows). (b) Later in development, the cell types that differentiate in the ventral region of the neural tube as a result of SHH‐mediated induction differ according to their position along the AP axis: motor neurons (green), hindbrain serotonergic raphe neurons (rn) and midbrain dopaminergic neurons (sn) all differentiate close to the floor plate under the influence of SHH but have distinct AP positions. SHH acts on cells that have different competence to respond; this is assigned early, as an aspect of their AP position. At this stage, SHH expression spreads into the telencephalon (T) and patterns its DV axis into medial and lateral ganglionic eminences. At this stage or earlier, the mid‐diencephalic junction (zona limitans intrathalamica, zli) also has a signalling function (red arrows in diencephalon, D).

Figure 5.

Cell pattern in the avian hindbrain. Specific subpopulations of motor neurons (circles) develop in specific rhombomeres (r). Branchiomotor neurons (mV, mVII and mIX) develop in adjacent rhombomere pairs and their axons leave the neural tube by way of exit points in the even‐numbered rhombomeres. Sensory axons from the cranial ganglia (gV, etc. shown on the left) enter the brain through the same exit points. Somatomotor neurons (IV, VI and XII) remain close to the floor plate (FP), whereas the branchiomotor neurons migrate laterally and dorsally. Exceptionally, efferent neurons of the VIIIth nerve, which develop only in r4, migrate contralaterally. i, isthumus and ov, otic vesicle.

Figure 6.

A comparison of the expression domains of the HOM‐C genes and their Hox homologues in the developing central nervous system of Drosophila and mouse, respectively. There are four paralogous clusters of Hox genes in vertebrates (Hox‐ad), only one of which (Hox‐b) is shown. The chromosomal order of genes as well as their individual structural identity has been conserved. Spatial and temporal colinearity of expression has also been conserved, with genes that lie 3′ on the chromosome being expressed more anteriorly and earlier than those that lie more 5′.

Figure 7.

Pattern formation on the dorsoventral axis of the spinal cord, seen in transverse section. (a) Normal development. The open neural plate (left), underlain by notochord (n), closes into a tube (right) in which motor neurons develop ventrally and specific markers (such as the antigen AC4, Pax3 and Pax6, blue) are expressed dorsally. (b) Experimental evidence for a signalling role for notochord and floor plate. When a supplementary notochord (n′) or floor plate (or Sonic hedgehog‐expressing cells) are grafted alongside the alar region of the neural plate, an additional floor plate and column of motor neurons are induced. Dorsal markers retreat from the zone of ectopic ventral induction. (c) When the notochord is removed at the neural plate stage, floor plate and motor neurons fail to appear. Dorsal markers spread ventrally as if normally suppressed by the notochord signal. (d) At the molecular level, a ventral gradient of SHH secreted by the notochord and floor plate is opposed by dorsal gradients of Wnts and BMPs. These morphogens influence positively (Wnts and BMPs) or negatively (SHH) the processing of the transcription factor Gli3 into the repressor Gli3R. As a result of these interactions, two opposing gradients result in distinct cell types in the neural tube (right).

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Further Reading

Briscoe J and Novitch BG (2008) Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube. Philosophical Transactions of the Royal Society. Series B, Biological Sciences 363: 57–70.

Brown M, Keynes R and Lumsden A (2001) Patterning the central nervous system. In: The Developing Brain, pp. 53–91. Oxford: Oxford University Press.

Glover JC, Renaud JS and Rijli FM (2006) Retinoic acid and hindbrain patterning. Journal of Neurobiology 66: 705–725.

Hoch RV, Rubinstein JL and Pleasure S (2009) Genes and signaling events that establish regional patterning of the mammalian forebrain. Seminars in Cell and Developmental Biology 20: 378–386.

Kiecker CK and Lumsden A (2005) Compartments and their boundaries in vertebrate brain development. Nature Reviews. Neuroscience 6: 553–564.

O'Leary DD, Chou SJ and Sahara S (2007) Area patterning of the mammalian cortex. Neuron 56: 252–269.

Roussigne M, Bianco IH, Wilson SW and Blader P (2009) Nodal signalling imposes left‐right asymmetry upon neurogenesis in the habenular nuclei. Development 136: 1549–1557.

Sanes DH, Reh TA and Harris WA (2006) Neural induction, polarity and segmentation. In: Development of the Nervous System, pp. 1–55. London: Elsevier Academic Press.

Stern CD (2006) Neural induction: 10 years on since the ‘default model’. Current Opinion in Cell Biology 18: 692–697.

Wolpert L (2007) Patterning the vertebrate body plan: axes and germ layers. In: Principles of Development, pp. 89–147. Oxford: Oxford University Press.

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Vermeren, Matthieu, and Keynes, Roger(Feb 2010) Vertebrate Central Nervous System: Pattern Formation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000794.pub2]