Icon module 22

Molecular mechanisms in the early development of the CNS

Listing of the abbreviations.

A harmonic development of the CNS requires a subtle interplay of elaborate regulation mechanisms. With regard to the understanding of the molecular mechanisms that steer the various developmental phases, substantial progress could be made over the past few years. To the early development of the CNS belong the processes of induction, proliferation, differentiation, cell migration and finally apoptosis. Progress in the understanding of these processes has led to numerous insights into the mode of action of certain molecules (transcription factors as well as intracellular signal transduction pathways) that are specific for certain embryonic developmental stages.

Investigations of the genomes of invertebrates and lower vertebrates (nematodes, drosophila, mice) have led to the identification of genes that guide embryonic development and probably also contribute to the development of the CNS in humans.

The embryonic development of the CNS could be traced back to the complex interactions between secreted molecules such as those of the superfamily of the TGF-β (transforming growth factors), the BMPs (bone morphogenetic proteins), the FGFs (fibroblast growth factors), the Wnts (wingless related), the CAMs (cellular adhesion molecules) as well as certain genes, especially the homeotic gene and of the Pax gene. These factors work in concert and via a specific spatio-temporal sequence. The activation of certain genes especially determines the differentiation of the neuroectodermal cells in neurons and glial cells. Moreover, exogenous factors such as folic acid and cholesterol are also indispensible for the organic development of the neural tube.


Differentiation of the primitive neural tube or neuroblastic transformation of the ectoderm

During gastrulation, the formation of the neural plate is induced by the notochord. This secretes substances such as follistatin, chordin and noggin that, for their part, suppress the secretion of BMP4 (bone morphogenetic protein). This protein is a growth factor in the TGF-β family that hinders the transformation of ectodermal cells into neuronal cells. More recent investigations have shown that FGF already suppresses the expression of BMP4 at an early stage.

Fig. 7 - Hypothetic scheme of the molecular mechanisms of
neuronal induction in vertebrate embryos

Fig. 7

The transformation of ectodermal cells into neuronal cells takes place spontaneously (by default). However, this differentiation is suppressed by tonic release of BMP from ectodermal cells.
During gastrulation substances like follistatin, chordin and noggin are released from the notochord whereby the activity of the BMP is suppressed on its side so that the differentiation of the neural plate occurs. Moreover, the FGFs hinder the transcription (mRNA) of the BMP already before gastrulation.

Cranio-caudal polarity of the neural tube

The differentiation of the neural tube is accompanied by a modulation of the gene expression in the notochord, in the prechordal plate, in the isthmic organizer and in the neural tube

  • At the level of the prosencephalon – where the notochord is absent –the prechordal plate effects the induction through the expression of transcription factors such as Emx (empty spiracle), Lim and Otx (orthodenticle).
  • In contrast, at the level of the mesencephalon and of the rhombencephalon this task is performed by the notochord and the paraxial mesoderm.
  • The development of the posterior part of the neural tube depends on the presence of other factors such as FGFs (fibroblast growth factors) as well as the Hox and cdx genes and retinoic acid
  • Finally the isthmic organizer is an important element in the craniocaudal segmentation of the brain. Namely, it expresses growth factors like FGF and Wnt and en (engrailed). Wnt and engrailed knock-out mice exhibit developmental disorders in the region of the mesencephalon and brain stem.
Fig. 8 - Molecular differentiation factors that are secreted in the neural tube

Prechordal plate
Isthmic organizer
Neural tube

Fig. 8

At the level of the prosencephalon the prechordal plate is responsible for the expression of transcription factors such as emx, lim and otx, while at the level of the mesencephalon and rhombencephalon this task falls to the notochord (expression of the hox and cdx genes). The isthmic organizer forms FGF, WNT and en.


Dorso-ventral polarity of the neural tube

While the determination of cranio-caudal polarity occurs in the neural plate stage, the dorso-ventral polarity is determined later. This is steered by the notochord, which induces the floor plate of the neural tube (or, more generally: the ventral region in the form of the basal motoric plate). This specialized region of the neural tube consists of cells with special properties. In particular, they form those chemotactic substances that steer the growth of the commissural fibers to the contralateral sides. Moreover, the notochord-floor-plate complex should be responsible for the early differentiation of the motor neurons (stage 13). Indeed, at this level, Shh (sonic hedgehog), a glycoprotein secreted by the notochord and later from the neural plate, represses the expression of genes like PAX 3 and PAX 7 that are responsible for the formation of the dorso-ventral polarity. Through this, the differentiation of motor neurons is made possible.

Concerning the dorsal region, the future sensory roof plates are formed, the dorsalization of which is due to the effects of a cascade of growth factors of the TGF-β family (dorsalin, activin, BMP4) as well as Wnts. These factors are responsible for the expression of dorsalizing genes like PAX 3 and HOX 7 (msx1). The spread of sensory cells ventrally, following an ablation of the notochord, indicates the suppressive effects of factors that stem from it.

Fig. 9 - Induction
of the motor neurons

  1. Ectoderm
  2. Roof of the neural tube
  3. Neural tube
  4. Floor of the neural tube
  5. Notochord

Fig. 10 - Induction
of the roof plate

Fig. 9

The secretion of Shh by the notochord-floor plate complex should induce the genesis of the motor neurons via repression of the dorsalizing genes like PAX 3 and PAX 7.

Fig. 10

The dorsalization of the roof of the neural tube (roof plate) results from the activation of a cascade of growth factors from the TGF-β family as well as of Wnts.

Fig. 11 - Expression map of the Pax gene products

Sensory neurons
Vegetative neurons
sensory and motor
Motor neurons

Fig. 12 - Expression map of the Pax gene products

Fig. 11

The Pax gene codes for transcription factors that play a prominent role in the development of the neural tube, namely the Pax 3/7 gene (roof plate) and Pax 6 (floor plate). A deficit in the expression of this gene leads to malformations (Waardenburg syndrome and aniridia).

Fig. 12

Expression map of the gene products of Pax in the mouse embryonic spinal cord (according to Chalepakis et al. 1991).