O8. Regulation of neuronal connectivity in the brain by ubiquitin signaling

Abstract

The assembly of neural circuits endows our brains with the ability to perform a vast array of functions from motor coordination to cognition. The goal of my laboratory is to identify the key mechanisms and principles that govern neuronal connectivity in brain development and disease. We have identified some of the first cell-intrinsic pathways that control axon, dendrite, and synapse development in the mammalian brain. Our studies reveal that the major cell cycle-regulated ubiquitin ligases Cdh1-APC and Cdc20-APC play crucial roles in neuronal morphogenesis and connectivity in postmitotic neurons in the mammalian brain. Cdh1-APC controls axon growth and patterning in the brain. In key follow-up studies, we have identified the transcriptional regulators SnoN and Id2 as critical substrates of Cdh1-APC in neurons. In other studies, we have discovered that the major mitotic ubiquitin ligase Cdc20-APC plays a key role in dendrite elaboration and growth in postmitotic neurons in the mammalian brain. Cdc20-APC operates at the centrosome in neurons to drive dendrite morphogenesis, suggesting a novel role for centrosomes in neuronal development. In recent studies, we have also discovered that Cdc20-APC drives the differentiation of presynaptic sites in the mammalian brain. At the meeting, I will present an update on the role of ubiquitin family pathways in neuronal connectivity.