Research
Drosophila Neural Development and Protein Degradation Control
1. The Drosophila peripheral nervous system is an excellent model to study neural development. One example is the specification of sensory neurons by proneural genes. My lab has also identified the proneural gene amos in controlling the formation of multi-dendritic (MD) neurons. The proneural proteins are bHLH transcriptional activators to promote neural precursor differentiation. We identified phyllopod (phyl) as a direct target gene of proneural proteins. The Phyl protein functions as a component of an ubiquitin ligase complex to degrade the neural repressor Tramtrack, thus promoting neural differentiation. Post-mitotic neurons grow extensively to form the axon and dendrites. We are studying the regulation in the formation of neuromuscular junctions and the elaboration of dendritic trees.
2. The ubiquitin (Ub)-proteasome degradation pathway is one major route to degrade cellular proteins. Ub ligases that recognize protein substrates for ubiquitination play the regulatory role in this process. We have taken genetic approaches to study the roles of cullin-Ring Ub ligases (CRLs) in Drosophila development. Cullins function as scaffold to organize CRL complexes. Cullin1 (Cul1) ligases promote C-terminal processing of Cubitus interruptus (Ci), the Hedgehog (Hh) signaling effector, during cell proliferation and Cullin3 (Cul3) ligases promote complete Ci degradation where Hh signaling is highly active. Cul3 regulates high Hh signaling activity in patterning the Drosophila compound eye. CRL activation requires covalent conjugation of the Ublike molecule Nedd8 onto cullins. We have shown that Nedd8 is essential for the activity of Cul1 and Cul3, two of the six cullins in the fly genome, to control substrate turnover. Nedd8 modification promotes CRL activity and also leads to degradation of Nedd8-modified cullins. Thus, removing Nedd8 recycles and preserves cullins in unmodified and stable forms. We further showed that Nedd8 processing enzyme DEN1 also functions to remove the Nedd8 moiety on many cellular proteins.
