Proneural genes and the specification of neural cell types

• Published in: Nature reviews. Neuroscience Vol. 3; no. 7; pp. 517 - 530
• Main Authors: Bertrand, Nicolas, Castro, Diogo S., Guillemot, François
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2002; Nature Publishing Group
• Subjects: Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell Differentiation - physiology; Cellular Biology; Drosophila; Gene Expression Regulation, Developmental - physiology; Genes; Helix-Loop-Helix Motifs; Humans; Insects; Invertebrates; Life Sciences; Nervous system; Neurobiology; Neurogenesis; Neurons - cytology; Neurons - physiology; Neurosciences; Proteins; review-article; Transcription factors; Transcription Factors - physiology; Vertebrates
• ISSN: 1471-003X; 1471-0048; 1471-0048; 1469-3178
• DOI: 10.1038/nrn874

Key Points Genetic studies in Drosophila and vertebrate models have provided evidence that a small number of 'proneural genes', which encode transcription factors of the basic helix–loop–helix (bHLH) class, are both necessary and sufficient to initiate the development of neuronal lineages and to promote the generation of progenitors that are committed to differentiation. Molecular analysis in Drosophila led to the isolation of four genes that regulate the early steps of neural development — achaete ( ac ), scute ( sc ), lethal of scute ( lsc ) and asense ( ase ). An additional proneural gene, atonal ( ato ), was identified in a screen to identify bHLH sequences related to that found in achaete-scute complex ( asc ) genes. Many genes that are related to asc and ato have been found in vertebrates. Proneural proteins bind DNA as heterodimeric complexes that are formed with ubiquitously expressed bHLH proteins, or E proteins, and most of them act as transcriptional activators. Mutation analysis in the mouse has so far established a clear proneural activity for only a few genes, namely Mash1 , Ngn1 and Ngn2 , and possibly Math1 and Math5 . However, these genes do not account for the selection of all neural progenitors, so it is likely that other genes with proneural activity remain to be identified. The mechanisms that underlie proneural function include: activation of the Notch signalling pathway, leading to the inhibition of proneural gene expression in adjacent cells; positive-feedback loops that maintain proneural gene expression; activation of neuronal-differentiation gene cascades that implement neuronal-differentiation programmes; inhibition of glial cell fates; and regulation of the cell cycle. In addition to their role in the initial selection and specification of neural progenitor cells, proneural proteins are also involved in neuronal-subtype specification. Future studies might reveal new roles for proneural genes that will help us to understand the coupling between proneural and subtype-differentiation programmes. Certain morphological, physiological and molecular characteristics are shared by all neurons. However, despite these similarities, neurons constitute the most diverse cell population of any organism. Recently, considerable attention has been focused on identifying the molecular mechanisms that underlie this cellular diversity. Parallel studies in Drosophila and vertebrates have revealed that proneural genes are key regulators of neurogenesis, coordinating the acquisition of a generic neuronal fate and of specific subtype identities that are appropriate for the location and time of neuronal generation. These studies reveal that, in spite of differences between invertebrate and vertebrate neural lineages, Drosophila and vertebrate proneural genes have remarkably similar roles.