A link between the nuclear-localized srGAP3 and the SWI/SNF chromatin remodeler Brg1

The Slit-Robo GTPase activating protein 3 (srGAP3) is an important modulator of actin cytoskeletal dynamics and has an important influence on a variety of neurodevelopmental processes. Mutations in the SRGAP3 gene on chromosome 3p25 have been found in patients with intellectual disability. Genome-wide association studies and behavioral assays of knockout mice had also revealed SRGAP3 as a risk gene for schizophrenia. We have recently shown that srGAP3 protein undergoes regulated shuttling between the cytoplasm and the nucleus during neuronal development. It is shown here that nuclear-localized srGAP3 interacts with the SWI/SNF remodeling factor Brg1. This interaction is mediated by the C-terminal of srGAP3 and the ATPase motif of Brg1. In the primary cultured rat cortical neurons, the levels of nuclear-localized srGAP3 and its interaction with Brg1 have a significant impact on dendrite complexity. Furthermore, the interaction between srGAP3 and Brg1 was also involved in valproic acid (VPA) -induced neuronal differentiation of Neuro2a cells. We then show that GTP-bound Rac1 and GAP-43 may be potential mediators of nuclear srGAP3 and Brg1. Our results not only indicate a novel signaling pathway that contributes to neuronal differentiation and dendrite morphology, but also implicate a novel molecular mechanism underlying srGAP3 regulation of gene expression.