Neural Development: bHLH Genes

Anna Philpott, University of Cambridge, Cambridge, UK

Published online: February 2010

DOI: 10.1002/9780470015902.a0000827.pub2

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 Xenopus NGN2 homologue X-Ngnr-1 and the Xenopus cyclin-dependent kinase inhibitor Xic1, during primary neurogenesis in Xenopus (first published in Vernon et al., 2006). Xenopus Neurogenin, X-Ngnr-1, both upregulates Delta resulting in activation of Notch in the adjacent cell, and drives differentiation via transcriptional upregulation of Xenopus MyT1 (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. (2006).
close
 References
    Artavanis-Tsakonas S, Matsuno K and Fortini ME (1995) Notch signaling. Science 268: 225–232.
    Campuzano S and Modolell J (1992) Patterning of the Drosophila nervous system: the achaete-scute gene complex. Trends in Genetics 8: 202–208.
    Dufton C, Marcora E, Chae JH et al. (2005) Context-dependent regulation of NeuroD activity and protein accumulation. Molecular and Cellular Neuroscience 28: 727–736.
    Fisher A and Caudy M (1998) The function of hairy-related bHLH repressor proteins in cell fate decisions. BioEssays 20: 298–306.
    Gohlke JM, Armant O, Parham FM et al. (2008) Characterization of the proneural gene regulatory network during mouse telencephalon development. BMC Biology 6: 15.
    Gomez-Skarmeta JL and Modolell J (2002) Iroquois genes: genomic organization and function in vertebrate neural development. Current Opinion in Genetics and Development 12: 403–408.
    Hand R, Bortone D, Mattar P et al. (2005) Phosphorylation of neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48: 45–62.
    Kageyama R, Ohtsuka T and Kobayashi T (2008) Roles of Hes genes in neural development. Development, Growth and Differentiation 50(suppl. 1): S97–S103.
    Lee JE (1997) Basic helix-loop-helix genes in neural development. Current Opinion in Neurobiology 7: 13–20.
    Lee S, Lee B, Lee JW and Lee SK (2009) Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron 62: 641–654.
    Lee SK and Pfaff SL (2003) Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors. Neuron 38: 731–745.
    Lewis J (1996) Neurogenic genes and vertebrate neurogenesis. Current Opinion in Neurobiology 6: 3–10.
    Longo A, Guanga GP and Rose RB (2008) Crystal structure of E47-NeuroD1/beta2 bHLH domain–DNA complex: heterodimer selectivity and DNA recognition. Biochemistry 47: 218–229.
    Ma YC, Song MR, Park JP et al. (2008) Regulation of motor neuron specification by phosphorylation of neurogenin 2. Neuron 58: 65–77.
    Nguyen L, Besson A, Heng JI et al. (2006) p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes and Development 20: 1511–1524.
    Powell LM and Jarman AP (2008) Context dependence of proneural bHLH proteins. Current Opinion in Genetics and Development 18: 411–417.
    Seo S and Kroll KL (2006) Geminin's double life: chromatin connections that regulate transcription at the transition from proliferation to differentiation. Cell Cycle 5: 374–379.
    Seo S, Lim JW, Yellajoshyula D, Chang LW and Kroll KL (2007) Neurogenin and NeuroD direct transcriptional targets and their regulatory enhancers. EMBO Journal 26: 5093–5108.
    Shimojo H, Ohtsuka T and Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58: 52–64.
    Simpson P (1996) A prepattern for sensory organs. Drosophila development. Current Biology 6: 948–950.
    Sugimori M, Nagao M, Bertrand N et al. (2007) Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development 134: 1617–1629.
    Vernon AE, Devine C and Philpott A (2003) The cdk inhibitor p27Xic1 is required for differentiation of primary neurones in Xenopus. Development 130: 85–92.
    Vernon AE, Movassagh M, Horan I et al. (2006) Notch targets the Cdk inhibitor Xic1 to regulate differentiation but not the cell cycle in neurons. EMBO Reports 7: 643–648.
    Vinals F, Reiriz J, Ambrosio S et al. (2004) BMP-2 decreases Mash1 stability by increasing Id1 expression. EMBO Journal 23: 3527–3537.
    Vosper JM, Fiore-Heriche CS, Horan I et al. (2007) Regulation of neurogenin stability by ubiquitin-mediated proteolysis. Biochemical Journal 407: 277–284.
 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.

Related Sub-Topics:

Neurons | Nervous System Development | Intracellular and Extracellular Signalling | Genes, Molecules and Cellular Processes | Development of Vertebrate Nervous System | Determination of Cell Fate | Cell Differentiation and Stem Cells
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Neural Development: bHLH Genes
 
How to Cite close
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]