Rho regulators in neuronal development and associated disorders

Friday, June 12th, 2015, 11:00 am
Elmore Auditorium
Linda Van Aelst, PhD, Cold Spring Harbor Laboratory
Ryohei Yasuda, PhD
(561) 972-9000

Event Information

Mutations in genes encoding Rho regulators, which include Rho-GEFs and Rho-GAPs, have been causally linked to multiple neurodevelopmental and/or neurological disorders, including intellectual disability, schizophrenia, and epilepsy. How defects in Rho regulators contribute to these disorders remains largely elusive. Here I discuss novel functions we uncovered for distinct Rho regulators in the development, maturation, and physiology of different neuronal cell types, with a particular focus on one of them, the DOCK180-family member DOCK7. Mutations in DOCK7 have been reported in individuals with epileptic encephalopathy and cortical blindness. The DOCK7 protein is expressed in various regions of the brain, including the cerebral cortex, where it is expressed in both excitatory and inhibitory neurons at levels that fluctuate during development. We discovered that DOCK7 plays a critical role in both the genesis and polarization of newborn excitatory neurons; perturbations in these processes are linked to cortical malformations and disorders of cortical organization. DOCK7 controls the genesis and polarization of these neurons by antagonizing TACC3 (transforming acidic coiled-coil-containing protein 3) function and promoting Rac activity, respectively.  We further discovered a critical role for DOCK7 in the morphological differentiation of a unique class of inhibitory neurons, called chandelier cells (ChCs); deficiencies of which have been implicated in epilepsy and schizophrenia. Interestingly, DOCK7 exerts its effects in ChCs in a Rac- and TACC3-independent manner. Instead, we found that DOCK7 promotes ChC differentiation by enhancing the activation of the schizophrenia-associated ErbB4 receptor tyrosine kinase. Thus, our findings unveil that DOCK7 executes several distinct functions in the brain, with relevance to common brain disorders, by engaging distinct signaling pathways.

This seminar is open to faculty, scientists, and students from Max Planck Florida Institute for Neuroscience (MPFI), Florida Atlantic University (FAU), and the Scripps Research Institute Florida, located on FAU’s John D. MacArthur Campus in Jupiter, Florida. If you belong to an institution outside of the Jupiter campus and would like to attend, please send a request to seminars@mpfi.org