Regulation of Neuronal Subtype Identity in the Vertebrate Neural Tube (Neuronal Subtype Identity Regulation)

Natascha Bushati, MRC‐National Institute for Medical Research, London, UK
James Briscoe, MRC‐National Institute for Medical Research, London, UK

Published online: February 2012

DOI: 10.1002/9780470015902.a0000795.pub2

Abstract

The vertebrate nervous system consists of many different neuronal cell types. Each has its own properties, axon projections and connection patterns. This diversity is established early during development and is required for the complex neuronal circuits that characterise the central nervous system. In the spinal cord, a series of events generates different neuronal subtypes, starting with the spatial patterning of neural progenitors. Extrinsic signals provide progenitors in the forming neural tube with positional identity, such that distinct types of progenitors express a unique combination of transcription factors. This transcriptional code determines neural progenitor identity. As progenitors differentiate, they generate distinct neuronal subtypes that are also characterised by a combinatorial transcriptional code. In addition to spatial patterning, other mechanisms contribute to the further diversification of differentiating neurons.

Key Concepts:

  • Secreted molecules provide positional information to neural progenitors in the developing neural tube.

  • Progenitors at different positions in the neural tube acquire distinct identities.

  • The identity of a progenitor is defined by the combination of transcription factors it expresses, which determines the gene expression profile of the progenitor.

  • An interplay between extrinsic signalling and the downstream gene network produces spatially discrete switches in progenitor identity.

  • Progenitors with distinct identities differentiate into post‐mitotic neurons with different subtype identities.

  • The identity of a neuron is determined by the transcriptional code of its progenitor and is itself defined by a separate transcriptional code.

  • In addition to spatial pattern, temporal changes in progenitor identity and signalling between differentiating cells increases neuronal diversity.

Keywords: neurons; spinal cord; morphogen; transcription factor; tissue patterning

Figure 1.

Development and structure of the neural tube. Schematics of transverse sections. (a) Invagination of the neural plate (shaded region) brings the lateral edges – the neural folds – together which then fuse to form the neural tube. The notochord expresses and secretes Shh (blue) to induce floor plate formation. (b) After neural tube closure, BMP family members (green) and other secreted factors are released from the dorsally located roof plate, whereas a ventral to dorsal gradient of the morphogen Shh is generated by the notochord and floor plate. Retinoic acid (RA) is released from the laterally located somites. (B′) The cells in the neural tube are organised in a pseudostratified epithelium. Mitotic nuclei are located apically and S‐phase nuclei basally.

Figure 2.

Patterning and generation of neuronal subtypes in the developing spinal cord. (a) Thirteen distinct progenitor domains (11 neural progenitor domains plus the floor plate and roof plate) are arranged along the dorsal ventral axis of the neural tube. Upon cell cycle exit, post‐mitotic cells migrate into the laterally located mantle layer. Each progenitor domain gives rise to one or several distinct subtypes of interneurons (V0–V3, dI1–dI6), motor neurons (MNs) or oligodendrocyte precursors (OLPs). (b) In the ventral neural tube, six progenitor domains (FP, p3, pMN, p2, p1, p0) are precisely established along the dorsal ventral axis. The expression of different combinations of transcription factors defines each progenitor domain.

Figure 3.

Ventral neural tube progenitor cells interpret Shh signalling via a gene regulatory network (GRN) of cross‐repressive interactions. Initially, early in development (t1), Pax6 (yellow) is expressed in progenitors and low levels of Shh induce low levels of Gli activity, which are not sufficient to activate Olig2 or Nkx2.2. As the concentration and range of the Shh gradient increases (t2−t3), higher levels of graded Gli activity (t2−t3) are induced. These peak (t3) and then decline (t4). As Gli activity increases, the progenitors respond by changing their TF expression profile according to the architecture of the GRN. First Olig2 is induced, which represses Pax6 (t2). Then Nkx2.2 is activated (t3), which represses Pax6 and Olig2 in the most ventral domain. Stable expression of the TFs is maintained even after Gli activity decreases (t4). (Based on Figure 7 in Balaskas et al., )

Figure 4.

Notch signalling during neural tube patterning and differentiation. (a) During early neural tube patterning, Notch ligands and proneural genes are expressed in an oscillatory manner in individual progenitors (striped pattern). (b) Cells are selected to exit the cell cycle and differentiate by lateral inhibition. In the absence of Notch signalling, proneural TFs are expressed in the prospective neuron (purple cell). This leads to up‐regulation of Notch ligands such as Delta or Jagged, which activate Notch in the neighbouring progenitor cells. In these cells, activated Notch inhibits proneural TFs, therefore differentiation is prevented and the cells remain proliferative.

Figure 5.

Additional mechanisms of neuronal subtype diversification. (a) The brachial LMC is subdivided into rostral and caudal domains defined by the expression of Hox5 and Hoxc8, respectively. In the Hoxc8 expressing domain, the patterns of Hox4, Hoxc6 and Hoxa7 expression are refined by cross‐repressive interactions. Once these are stabilised, cells expressing the same Hox TF cluster into discrete pools (red, green and blue), which innervate a single target muscle. (Based on Figure 6.4 in Dasen and Jessell, ) (b) The p2 progenitor domain gives rise to V2a and V2b interneurons. In the prospective V2a cell, Foxn4 induces the expression of the Notch ligand Dll4. This activates Notch in the neighbouring future V2b cell, leading to expression of Scl and inducing V2b identity. (c) After giving rise to motor neurons, pMN progenitors switch to oligodendrocyte production. The Notch ligand Jag2 is induced in the differentiating motor neuron, which activates Notch in neighbouring pMN cells, ensuring that the pMN pool is not depleted. Once the Jag2 cells have all differentiated into MNs, Notch signalling is downregulated and oligodendrocyte progenitors (OLPs) differentiate from pMNs.

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Further Reading

Gilbert SF (2010) Developmental Biology, 9th edn. Boston: Sinauer Associates.

Related Sub-Topics:

Organisation of the Nervous System | Nervous System Development | Development of Vertebrate Nervous System
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Article Title: Regulation of Neuronal Subtype Identity in the Vertebrate Neural Tube (Neuronal Subtype Identity Regulation)
 
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Bushati, Natascha, and Briscoe, James(Feb 2012) Regulation of Neuronal Subtype Identity in the Vertebrate Neural Tube (Neuronal Subtype Identity Regulation). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000795.pub2]