Function of Arp6 and H2av in Drosophila Sensory Organ Patterning and Development

Neurogenesis requires precise control of gene transcription. The bHLH proneural proteins are highly conserved transcriptional activators, and play key roles in neurogenesis from fly to human. In Drosophila, the proneural proteins Achaetae (Ac) and Scute (Sc) promote external sensory (ES) organ formation through transcriptional activation. Previous study in our lab showed that actin, the major component of the cytoskeleton, associates with Ac and Sc in nucleus and is required for Ac and Sc to activate transcription. In addition to actin, we recently discovered that the actin-related protein 6 (Arp6), a member of the actin family protein, associate with Ac and Sc in Drosophila cells. Arp6 is highly conserved from yeast to human, and studies of yeast and human Arp6 show that it is primarily localized in nucleus. We also found that it is Arp6, but not other nuclear Arps including Arp4, Arp5 and Arp8, associates with proneural proteins. Analysis of Arp6 loss-of-function knock-in allele generated by CRISPER/Cas9 showed that Arp6 is required for timely high-level Ac expression in sensory organ precursors (SOPs). Results from yeast and plant show that Arp6 is a component of SWR1 chromatin remodeling complex that is required for H2Av variant exchange in the nucleosome. In this grant, we propose to study whether Arp6 promotes high-level Ac auto-regulation in SOPs through H2Av and the SWR1 ATPase Domino. Our study in S2 cells also showed that Arp6 stabilizes Ac protein. We will also explore the possible role of Arp6 in regulation of proneural protein stability. The ES organs on the fly notum, especially the microchaetae, are arranged in rows in a precise pattern. Notch pathway is required for ES organ patterning through both the cell contact-dependent Notch signaling, and the filopodia-mediated longrange Notch signaling. In Arp6 mutant, the microchaetal density was increased, suggesting that Arp6 is required for the long-range lateral inhibition transducing through the filopodia. In addition, Arp6 is also required for wing margin formation, a process mediated by the Notch pathway. In the second part of this grant, we propose to investigate the mechanism of Arp6 and H2Av in filopodia-mediated lateral inhibition and in Notch signaling.

Project ID:PA10601-0184
External Project ID:MOST104-2311-B182-004-MY3