Members of the Bacurd (BTB-domain containing adaptor for Cul3-mediated RhoA degradation) proteins are implicated in neurological disorders such as Autism Spectrum Disorders, but their functions during brain development remain poorly understood. In this study, we describe a novel role for Bacurd2 during mouse cerebral cortical development, with forced expression and knockdown of Bacurd2 significantly disrupting the migration of cortical cells in embryonic mouse brains. In neuritogenic assays, overexpression of Bacurd2 in PC12 cells results in significant impairment of neuritogenesis. We further demonstrate the protein-protein interacting terminal domains of Bacurd2 to possess complementary functions for neuritogenesis, with Rnd2 and Cul3 as interacting partners to its carboxy and amino termini, respectively. Although suppression of Rnd2 expression by RNAi impairs cell migration in vivo[2,3], we were not able to rescue the migration defect of Rnd2-deficient cortical neurons with wild type Bacurd2 alone but only with chimeric Bacurd2 polypeptides that localise to the perinuclear region of Rnd2. Further analysis of the migration profile showed defective entry of Rnd2-deficient cells into the cortical plate when co-electroporated with chimeric Bacurd2 polypeptide that lack Cul3 binding ability. Our results highlight a novel mechanism for Cul3-Bacurd2-Rnd2 interaction that regulates morphology of neurons, as well as mediating radial migration of immature neurons during cerebral cortical development.

Bacurd2 is a novel interacting partner to Rnd2 which controls radial migration within the developing mammalian cerebral cortex