Neural Development: bHLH Genes

Abstract

Transcription factors of the basic helix–loop–helix (bHLH) class are involved in the determination of precursor cells towards neural (proneural) and other cell fates. The proneural members of this class constitute a particular subset of bHLH proteins that are arranged in a cascade that affects different stages of neuronal commitment and differentiation, and act in a combinatorial code along with other transcription factors to specify neuronal identity. Proneural proteins themselves are a target of regulation by ID and HES proteins among others, and are involved in setting up a negative feedback pathway of lateral inhibition involving NOTCH and DELTA signalling. In addition, the activities of bHLHs are also subject to control by posttranslational modification and degradation. Finally, recent analyses have begun to identify the direct downstream targets of bHLH genes in the nervous system, and this is shedding light on the mechanisms ensuring specificity of the individual bHLH proteins.

Key concepts:

  • bHLH proneural transcription factors have multiple direct downstream transcriptional targets including other transcription factors, signal transducers and cytoskeletal modifiers.

  • bHLH proneural transcription factors act in a combinatorial code to confer neuronal subtype identity.

  • bHLH transcription factors are regulated posttranslationally by mechanisms including phosphorylation and ubiquitin‐mediated proteolysis.

  • bHLH proneural transcription factors have multiple downstream targets that orchestrate neural differentiation.

  • Negative regulators of bHLH proneural proteins such as HES and ID proteins act by dimerizing with and sequestering E protein partners.

  • Lateral inhibition mediated by the NOTCH–DELTA pathway limits the number of neurons that differentiate from the pool of neuronal precursors.

Keywords: proneural; neurogenesis; transcription factor; lateral inhibition; differentiation; determination

Figure 1.

A typical cascade of proneural genes in a Drosophila external sense organ. The iroquois (Iro) genes positively regulate achaete (ac) and scute (sc), defining the proneural cluster. Hairy represses the proneural genes outside the cluster. Achaete and scute dimerize with daughterless (da) to drive asense (ase) expression leading to neural specification, but within the proneural cluster, the Notch pathway through activation of E(spl) repressors, limits the expression and function of ac and sc to a single cell. Extramachrochaete (emc), another pathway inhibitor, reinforces this pattern.

Figure 2.

Model illustrating the interactions between the Notch pathway, the XenopusNGN2 homologue X‐Ngnr‐1 and the Xenopuscyclin‐dependent kinase inhibitor Xic1, during primary neurogenesis in Xenopus (first published in Vernon et al., ). XenopusNeurogenin, X‐Ngnr‐1, both upregulates Delta resulting in activation of Notch in the adjacent cell, and drives differentiation via transcriptional upregulation of XenopusMyT1 (xMyT1) and NeuroD. The Xenopus cdki p27Xic1 stabilizes X‐Ngnr‐1, and potentiates the neuronal differentiation arm of this network. Reproduced from Vernon et al..

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Further Reading

Guillemot F (2007) Cell fate specification in the mammalian telencephalon. Progress in Neurobiology 83: 37–52.

Kageyama R, Ohtsuka T, Hatakeyama J and Ohsawa R (2005) Roles of bHLH genes in neural stem cell differentiation. Experimental Cell Research 306: 343–348.

Quan XJ and Hassan BA (2005) From skin to nerve: flies, vertebrates and the first helix. Cellular and Molecular Life Sciences 62: 2036–2049.

Yan RT, Ma W, Liang L and Wang SZ (2005) bHLH genes and retinal cell fate specification. Molecular Neurobiology 32: 157–171.

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Philpott, Anna(Feb 2010) Neural Development: bHLH Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000827.pub2]