A novel transcriptional network of broadly expressed HLH genes: Regulating tissue specific cell fates

Neural patterning is attributed to highly regulated transcription of specific proneural bHLH transcription factors (Scute, Achaete, Atonal in Drosophila and their homologs Mash, Math, Neurogenins etc.) that define neuronal progenitor cells. These specific bHLH transcription factors function only as obligate heterodimers with one of the broadly expressed bHLH proteins or E-proteins [Daughterless (Da), EU, E47, E2-2, HEB]. bHLH protein functions are also modulated by another class of broadly expressed HLH proteins or Id-proteins [Extramacrochaetae (Emc), Id1-4], which lack the DNA-binding basic domain and inhibit bHLH transcription factors by forming inactive heterodimers.;We discovered a novel cross-interacting regulatory network that locks together the widespread expressions of the E-protein and Id-protein in Drosophila, Da and Emc, independent of any spatiotemporally expressed bHLH protein activity. The key features of this network are that da and emc are both transcriptional targets of the Da protein. Emc inhibits Da activity and prevents runaway da upregulation through an autoregulatory enhancer. These coupled positive and negative feedback loops homeostatically maintain the widespread Emc expression that keeps the Da expression low, through buffering Da activity, opposing bHLH protein dependent differentiation in most imaginal disc cells while enhancing cell growth and survival. This network thereby links control of cell proliferation to differentiation.;In the neurogenic ectoderm extracellular signals (Decapentaplegic and Hedgehog in the developing eye) spatiotemporally repress emc, permitting Da levels to rise and facilitate neural differentiation. This regulatory network thereby marks proneural regions independently of proneural bHLH activity.;Our studies indicate that the function of this network is not limited to the control of proliferation and proneural region specification, but is also required to confer fate identity on already specified neuronal cells. We describe a role for Emc in the R7 photoreceptor fate choice through its ability to buffer Da activity.;In conclusion, our studies established a novel cross-interacting network that regulates expression and activities of the E-proteins and Id-proteins. Homologous networks may regulate other processes that depend on specific bHLH transcription factors, such as myogenesis, and may be conserved in vertebrate systems.