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The generation of neural tissue involves an inductive signal from the underlying chordamesoderm (notochord), termed the ‘organizer’. The observation by Spemann in 1925 that, in intact amphibian embryos, the presence of an organizer caused ectodermal cells to form nervous tissue, whereas in its absence they formed epidermis, led to the discovery of neural induction. However, experiments performed much later in the century revealed that when ectodermal cells were dissociated they also gave rise to neural tissue. The paradox was resolved by the finding that intact ectodermal tissue is prevented from becoming neural by an inhibitory signal(s) that is diluted out when cells are dissociated. Many lines of evidence now indicate that this inhibitory signal is mediated by members of a family of secreted proteins, the bone morphogenetic proteins (BMP). These molecules are found throughout ectodermal tissue during early development, and their inhibitory effect is antagonized by several neural inducers which are present within the organizer, i.e. noggin, chordin and follistatin. Each of these factors is capable of blocking BMP signalling, in some cases by preventing it from binding to its receptor(s).

The regional pattern of the nervous system is induced before and during neural tube closure. Early concepts about regional patterning envisaged that regionalization within mesenchymal populations which transmit inductive signals to the ectoderm impose a similar mosaic of positional values on the overlying neural plate. For example, transplantation of caudal mesenchyme beneath the neural plate in Amphibia induced spinal cord, whereas rostral mesenchyme induced brain, as assessed by the morphology of the neuroepithelial vesicles. However, later work indicated a more complex scenario in which organizer grafts from early embryos induced mainly head structures, while later grafts induced mainly trunk structures. Subsequent molecular data have tended to support a model in which neural-inducing factors released by the organizer such as noggin, chordin and follistatin, neuralize the ectoderm and promote a mainly rostral neural identity. Later secreted signals then act to caudalize this rostral neural tissue, setting up an entire array of axial values along the neural tube. Candidates for these later, caudalizing, signals have been shown to be retinoic acid, fibroblast growth factors and the WNT secreted proteins, which are present in the paraxial mesenchyme and later in its derivatives, the somites. This combination of signals does not seem to be sufficient to produce the most rostral, forebrain structures. Other secreted proteins resident in the rostralmost part of the earliest ingressing axial populations of endoderm and mesenchyme are also capable of inducing markers of forebrain identity from ectodermal cells (Withington, Beddington & Cooke 2001).

As the neural tube grows and is modified in shape, a number of mechanisms refine the crude rostrocaudal pattern which has been imposed during neurulation. Molecules which diffuse from tissues adjacent to the neural tube such as the somites have patterning influences. The neural tube possesses a number of intrinsic signalling centres, such as the midbrain–hindbrain boundary, which produce diffusible molecules capable of influencing tissue development at a distance. In this way extrinsic and intrinsic factors serve to subdivide the neural tube into a number of fairly large domains, on which local influences can then act. Domains are distinguished by their expression of particular transcription factors, which in many cases have been causally related to the development of particular regions. Examples of such genes are the Hox family which are expressed in the spinal cord and hindbrain, and the Dlx, Emx and Otx families of genes which are expressed in various regions of the forebrain. All of these are developmental control genes which lie high up in the hierarchy, and are capable of initiating cascades of expression of other genes to create a more fine-grained pattern of cellular differentiation. In contrast to the aforementioned secreted molecules, these genes encode proteins which are retained in the cell nucleus, and so can act on DNA to induce or repress further gene expression.

Segmentation in the neural tube

The early neural tube is visibly divided into segments, termed neuromeres, by shallow transverse folds which extend perpendicular to its long axis. Primary neuromeres can be identified at stage 9, and 16 secondary neuromeres are present at stage 14. They are especially noted in the rhombencephalon, where they are termed rhombomeres; they have now been shown to constitute crucial units of pattern formation. Domains of expression of developmental control genes abut rhombomere boundaries; single cell labelling experiments have revealed that cells within rhombomeres form segregated non-mixing populations (Fig. 24.16). The neural crest also shows intrinsic segmentation in the rhombencephalon, and is segregated into streams at its point of origin in the dorsal neural tube. This may represent a mechanism whereby morphogenetic specification of the premigratory neural crest cells is conveyed to the pharyngeal arches (see Fig. 12.4). Although these segmental units lose their morphological prominence with subsequent development, they represent the fundamental ground plan of this part of the neuraxis, creating a series of semi-autonomous units within which local variations in patterning can then develop. The consequences of early segmentation for events later in development, such as the formation of definitive neuronal nuclei within the brain stem, and of peripheral axonal projections remain to be explored.


Fig. 24.16  Hox gene expression domains in the branchiorhombomeric area in the mouse embryo at E9.5. The arrows indicate neural crest cells migrating from the rhombencephalon and midbrain. At the former level they are shaded to indicate the Hox genes they express. The same combination of Hox genes is expressed in the rhombomeres and in the superficial ectoderm of the pharyngeal arches at the corresponding rostrocaudal levels. The four Hox clusters are represented below.
(Modified by permission from the Annual Review of Cell and Developmental Biology, Volume 8, 1992 by Annual Reviews www.annualreviews.org.)

Other brain regions are not segmented in quite the same way as the hindbrain. However, morphological boundaries, domains of cell lineage restriction and of cell mixing, and regions of gene expression that abut sharp boundaries, are found in the diencephalon and telencephalon. It is thus likely that compartmentation of cell groups with some, if not all, the features of rhombomeres plays an important role in the formation of various brain regions.

The significance of intrinsic segmentation in the hindbrain is underlined by the absence of overt segmentation of the adjacent paraxial mesenchyme. There is no firm evidence for intrinsic segmentation in the spinal cord. Instead, segmentation of the neural crest, motor axons, and thus eventually the spinal nerves, is dependent on the segmentation of the neighbouring somites. Both neural crest cell migration and motor axon outgrowth occur through only the rostral and not the caudal sclerotome of each somite, so that dorsal root ganglia form only at intervals. The caudal sclerotome possesses inhibitory properties that deter neural crest cells and motor axons from entering. This illustrates the general principle that the nervous system is closely interlocked, in terms of morphogenesis, with the ‘periphery’, i.e. surrounding non-nervous structures, and each is dependent upon the other for its effective structural and functional maturation.

Genes such as the Hox and Pax gene families, which encode transcription factor proteins, show intriguing expression patterns within the nervous system. Genes of the Hox-b cluster, for example, are expressed throughout the caudal neural tube, and up to discrete limits in the hindbrain that coincide with rhombomere boundaries. The ordering of these genes within a cluster on the chromosome (5′-3′) is the same as the caudal to rostral limits of expression of consecutive genes. This characteristic pattern is surprisingly similar in fish, frogs, birds and mammals. Hox genes play a role in patterning not only of the neural tube but also of much of the head region, consistent with their expression in neural crest cells, and within the pharyngeal arches. Disruption of Hox a-3 gene in mice mimics DiGeorge’s syndrome, a congenital human disorder characterized by the absence (or near absence) of the thymus, parathyroid and thyroid glands, by the hypotrophy of the walls of the arteries derived from the aortic arches, and by subsequent conotruncal cardiac malformations. Some Pax genes are expressed in different dorsoventral domains within the neural tube. Pax-3 is expressed in the alar lamina, including the neural crest, while Pax-6 is expressed in the intermediate plate. The Pax-3 gene has the same chromosomal localization as the mouse mutation Splotch and the affected locus in the human Waardenburg’s syndrome, both of which are characterized by neural crest disturbances with pigmentation disorders and occasional neural tube defects. Both Hox and Pax genes have restricted expression patterns with respect to the rostrocaudal and the dorsoventral axes of the neural tube, consistent with roles in positional specification. (For reviews of the expression patterns of these genes see Krumlauf et al 1993.)

While craniocaudal positional values are probably conferred on the neuroepithelium at the neural plate or early neural tube stage, dorsoventral positional values may become fixed later. The development of the dorsoventral axis is heavily influenced by the presence of the underlying notochord. The notochord induces the ventral midline of the neural tube, the floor plate. This specialized region consists of a strip of non-neural cells with distinctive adhesive and functional properties. Notochord and floor plate together participate in inducing the differentiation of the motor columns. Motor neurone differentiation occurs early, giving some grounds for the idea of a ventral to dorsal wave of differentiation. The notochord/floor plate complex may also be responsible for allotting the values of more dorsal cell types within the tube (Fig. 24.7). For example, the dorsal domain of expression of Pax-3 extends more ventrally in embryos experimentally deprived of notochord and floor plate, while grafting an extra notochord adjacent to the dorsal neural tube leads to a repression of Pax-3 expression.

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