Similar but unique: shared and individual roles for gamma-Pcdhs in cortical development

Development of the cerebral cortex requires highly regulated operations including extension of neuronal processes and establishment of mature neuron-to-neuron contacts. Disruption to these processes are associated with neurodevelopmental disorders such as autism spectrum disorder, intellectual disability, and schizophrenia. Therefore, understanding the molecular mechanisms through which these processes are regulated is crucial not only for our understanding of neurodevelopment, but also for the development of potential therapeutic interventions for related neurodevelopmental disorders.

The γ-Protocadherins, a family of 22 cell adhesion molecules that link neurons together, have been previously found to be required for the proper formation of neuronal morphology and connectivity. The combinatorial expression of these 22 γ-Pcdhs is thought to impart an individual identity or “neuronal barcode” to facilitate correct neural circuit formation. Mice lacking all γ-Pcdhs in the primary neurons of the cortex exhibit decreased complexity of dendritic arbors and increased excitatory synapse density. In this dissertation, I focus on how shared roles, mediated by multiple γ-Pcdhs, and unique roles, mediated by individual γ-Pcdhs, regulate various elements of neurodevelopment. First, I demonstrate how multiple γ-Pcdhs interact with another cell-adhesion molecule called Neuroligin-2, and negatively regulate inhibitory synapse formation. Next, I describe my work identifying an isoform-specific role for one γ-Pcdh protein, called γC3, in dendritic arbor formation through interactions with the scaffolding protein Axin1. These studies advance our knowledge on how the complex nature of the γ-Pcdh family regulates neurodevelopment.