A Ubiquitin Ligase Signaling Mechanism Regulates Golgi Morphology and Dendrite Patterning

The elaboration of dendrites in neurons requires secretory trafficking through the Golgi apparatus, but the mechanisms that govern Golgi function in the establishment of neuronal morphogenesis in the brain have remained largely unexplored. I have characterized the function of an E3 ubiquitin ligase Cul7Fbxw8 that I have found localizes to the Golgi complex in mammalian brain neurons. Inhibition of Cul7Fbxw8 by independent approaches including Fbxw8 knockdown reveals that Cul7Fbxw8 is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo. Inhibition of Cul7Fbxw8 also dramatically impairs the morphology of the Golgi complex leading to deficient secretory trafficking in neurons. Using an immunoprecipitation/mass spectrometry screening approach, I have also uncovered the cytoskeletal adaptor protein OBSL1 as a critical regulator of Cul7Fbxw8 in Golgi morphogenesis and dendrite elaboration. OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus. Accordingly, OBSL1 is required for the morphogenesis of the Golgi apparatus and the elaboration of dendrites. Finally, I have identified the Golgi protein Grasp65 as a novel and physiologically relevant substrate of Cu17Fbxw8 in the control of Golgi and dendrite morphogenesis in neurons. Collectively, these findings define a novel OBSL1-regulated Cul7Fbxw8 ubiquitin signaling mechanism that orchestrates the morphogenesis of the Golgi apparatus and patterning of dendrites, with fundamental implications for our understanding of brain development.