The role of E3 ubiquitin ligase FBXO31-SCF in neuronal morphogenesis

Abstract

Neuronal development is coordinated by the interplay of extrinsic cues and intrinsic factors. These extrinsic cues act through multiple intracellular signaling pathways to regulate the cytoskeleton machinery of the neuron that is essential during neuronal morphogenesis. Recent evidence identifies the ubiquitin proteasome system (UPS) as a crucial cell-intrinsic regulator of neuronal development. The Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase and in particular the substrate-recruiting adaptor subunit F-box proteins have emerged as essential modulators of diverse aspects of neuronal development including progenitor proliferation, migration, axon and dendrite growth and synaptogenesis. In this study, I identified the brain-enriched centrosomal F-box protein FBXO31-SCF as a novel regulator of neuronal morphogenesis both in vitro and in the developing cerebellum. While my study identifies FBXO31-SCF as a regulator of axonal identity, I also found that FBXO31-SCF promotes of axon and dendrite growth in neurons. To gain mechanistic insight into the FBXO31-regulated phenotypes, I uncovered the polarity protein Par6c as a novel interaction partner and a bona de substrate of FBXO31. Further analysis revealed that FBXO31-SCF acts upstream of polarity complex protein Par6c to regulate axon growth but not dendrite growth in neurons. Taken together, my study gives a systematic insight into FBXO31-regulated events in developing neurons and thus introduces the E3 ubiquitin ligase FBXO31-SCF as a key regulator of neuronal development.