Regulation and functions of the drosophila ID protein extra macrochaetae in neural development
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The well-conserved basic helix-loop-helix (bHLH) genes encode dimeric transcription factors essential for many developmental events. The activities of tissue-specific bHLH transcription factors require their heterodimerization partners E-proteins, whereas Inhibitor of Differentiation (ID) proteins inhibit their activities by competitively forming inactive heterodimers with them. The balance between E proteins and ID proteins is thought to define the cellular competence for differentiation. A classic example is that Extra macrochaetae (Emc), the sole Drosophila ID protein, is lowered in proneural regions where neural progenitor cells arise, which has been thought to independently define proneural prepatterns with increased sensitivity to proneural bHLH genes prior to their expressions. Our studies began by characterizing emc transcriptional and post-transcriptional regulation and identifying regulatory elements with molecularly defined CRISPR alleles. We later discovered that, instead of contribution from a homeostatic transcriptional feedback, Emc protein is largely regulated post-translationally. Emc protein levels are quantitatively determined by Da, the sole Drosophila E protein, through dimerization. In proneural regions, proneural bHLH proteins including Atonal (Ato) and Achaete-Scute Complex (AS-C) proteins displace Emc from the Da/Emc complex by sequestering Da into proneural bHLH/Da dimers. Together with concurrent mechanisms that differentially regulate emc in proneural regions, the dynamic replacement of Emc favors proneural bHLH/Da heterodimer formation and therefore higher proneural activities.;In addition, inspired by the compelling evidence linking E proteins and ID proteins to numerous cancers and neurocognitive disorders, we also explored their roles in cell cycle regulation and neuronal morphogenesis. Both Da and Ato are non-autonomously required for cell cycle progression during the Second Mitotic Wave in Drosophila eye development, whereas Emc is dispensable. To gain insights in possible mechanisms underlying E-proteins-associated neurocognitive diseases, we examined roles of Da and Emc in dendritic morphogenesis and discovered that Da gain-of-function significantly reduces dendritic arborization in Class IV multidendritic neurons.;In conclusion, our results challenge the prevailing notion that Emc defines a prepattern for neurogenesis independently of proneural genes; instead, we present evidence that Emc expression pattern is a consequence of proneural bHLH expressions and that itself may reflect contribution from preexisting patterns. Dynamic replacements of distinct dimer species that change protein stability and function could also be a general feature of bHLH-mediated developmental events. Finally, our findings may shed light on the pathogenesis of cancers and neurocognitive disorders.
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