Proneural genes

Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells. Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells. The proneural genes are expressed in groups of cells (proneural clusters) from which one progenitor cell – typically the one in the middle – will be singled out, leading to the formation of many different types of neurons in the central and peripheral nervous systems. Proneural genes encode a group of bHLH proteins that play crucial roles in controlling cell fate in a variety of tissue types. Basic helix-loop-helix proteins are characterized by two alpha helixes separated by a loop. The helixes mediate dimerization, and the adjacent basic region is required for DNA binding. The human genome contains approximately 125 bHLH factors. The proneural genes were first identified in the 1920s, when mutant flies that lacked subsets of external sense organs or bristles were found. Later on, in the 1970s, the achaete-scute complex, a complex of genes that are involved in regulating the early steps of neural development in Drosophila, were identified. Using molecular tools it was possible to isolate the first four genes of this complex: achaete (ac), scute (sc), lethal of scute (lsc) and asense (ase). Another proneural gene, atonal (ato) was isolated more recently and two ato-related genes, amos and cato, were later-isolated, defining a second family of proneural genes – atonal complex. Recently, the first homologue of the fly proneural genes to be found in mammals was mash1. This list refers to bHLH proteins found in invertebrates and vertebrates. They are grouped in distinct families on the basis of closer sequence similarities in the bHLH domain: Genes of the ASC and Ngn families, and possibly members of the family of ato homologues, have a similar proneural function in vertebrates to that of their Drosophila counterparts, whereas other neural bHLH genes are involved in specifying neuronal fates or in neuronal differentiation, but have no proneural role. Proneural proteins bind DNA as heterodimeric complexes that are formed by bHLH proteins or E proteins. Because heterodimerization is a prerequisite for DNA binding, factors that interfere with dimerization effectively act as passive repressors of proneural gene activity. Proneural proteins specifically bind DNA sequences that contain a core hexanucleotide motif, CANNTG, known as an E-box. The basic region and helix 1 of the bHLH domain form a long alpha-helix that is connected with the loop region to helix 2. Direct contacts between bHLH residues and DNA are responsible for the common ability of neural bHLH proteins to bind to the core E-boxsequence. The cells within a cluster that express a proneural gene (called a proneural cluster) can be thought of as cells of an equivalence group. Within a proneural cluster, the cells compete with each other, such that only a subset of cells is singled out to develop into neuronal precursors. This singling out process is mediated by cell-cell interactions interpreted through the action of neurogenic genes. In neuroectoderm, neurogenic genes are required to single out cells from within proneural clusters to form neuronal precursors, leaving the remaining cells of proneural clusters to develop into epidermal cells. Proneural genes may function in analogous fashions in vertebrates and invertebrates, specifically they were implicated in early neurogenesis. Although proneural proteins are responsible for trigger neurogenesis, different proteins are required for different neural and/or glial cell types. This implies that each of these proteins is capable of regulating both common target genes for neurogenesis and unique target genes for neuronal subtype characteristics. Proneural bHLH transcription factors, not only drive neurogenesis by activating the expression of a cascade of neuronal genes, but they inhibit the expression of glial genes. Neural bHLH genes have different functions depending on: the sensitivity to lateral inhibition, which determines if a cell becomes epidermal or neuronal, and whether the gene is expressed in the CNS before or after the terminal mitosis. Proneural genes promote neurogenesis and inhibit gliogenesis but some neurogenic factors can regulate both of these processes, depending on the proneural genes concentration. For example, BMPs (Bone Morphogenetic Proteins) promote neurogenesis in progenitors that express high levels of Neurogenin-1 and gliogenesis in progenitors that express low levels of Neurogenin-1.Gliogenesis processes depend on low concentrations or delection of proneural genes and can be accelerated depending on which proneural genes are affected. In Drosophila, proneural genes are first expressed in quiescent ectodermal cells that have both epidermal and neuronal potential. Proneural activity results in the selection of progenitors that are committed to a neural fate but remain multipotent, with sense organ progenitors giving rise to neurons, glia and other non-neuronal cell types. Additionally, some neuroblasts of the central nervous system also generate both neurons and glia. Progenitors of the peripheral and central nervous system only begin to divide after proneural gene expression has subsided. Proneural genes are first expressed in neuroepithelial cells that are already specified for a neural fate and are self-renewing. Proneural activity results in the generation and delamination of progenitors that are restricted to the neuronal fate and have a limited mitotic potential. In some lineages, at least, proneural genes are involved in the commitment of neural progenitors to the neuronal fate at the expense of a glial fate.