Decreased synaptic connectivity in the cerebral cortex contributes to the pathology of autism, mental retardation, and schizophrenia in humans (Selemon and Goldman-Rakic, 1999; Kaufmann and Moser, 2000; Ramakers, 2002). A major goal of neuroscience is to determine how dendritic and axonal processes navigate the extracellular milieu to form synapses with their appropriate targets. The nascent tips of growing axons and dendrites must recognize specific environmental cues and rearrange their cytoskeleton to follow the appropriate path. My laboratory is studying how the related Abl and Arg (Abl-related gene) nonreceptor tyrosine kinases relay information from cell surface adhesion receptors promote cytoskeletal rearrangements in developing neurons.

Abl family kinases regulate adhesion-dependent dendrite formation.

Our recent studies indicate that both hippocampal CA1 and cortical layer V pyramidal neurons exhibit significantly decreased dendrite arbor complexities in mice whose brains lack Arg (arg^-/- mice) or both Abl and Arg (abl^-/-arg^-/-). Interestingly, adhesion to Laminin-1 potentiates neurite outgrowth and branching from wild type, but not arg^-/- cortical neurons in culture. These experiments provide evidence that Abl family kinases are essential regulators of dendrite morphogenesis in response to adhesive cues. Our first Aim will be to examine which receptors for Laminin-1 require Arg to mediate the adhesion-dependent affects on dendrite morphogenesis.

Arg phophorylates the cytoskeletal regulatory protein p190RhoGAP in the developing brain.

Rho family GTPases (RhoA, Rac1 and Cdc42) act as molecular switches that control actin cytoskeletal dynamics by cycling between an inactive GDP-bound form and an active GTP-bound form. Rho family GTPases are controlled by two classes of regulatory molecules: guanine nucleotide exchange factors (GEFs) that activate Rho family GTPases by promoting exchange of GTP for GDP and GTPase activating proteins (GAPs) that inhibit Rho family GTPases by stimulating Rho to hydrolyze GTP (Kaibuchi et al., 1999). We have also recently shown that the Rho inhibitor p190RhoGAP is a major substrate of Arg in the developing mouse brain (Hernandez et al., 2004). Arg phosphorylates p190RhoGAP upon adhesion of fibroblasts or neurons to fibronectin or laminin, respectively. Importantly, Arg phosphorylation of p190RhoGAP on tyrosine 1105 activates p190RhoGAP to inhibit Rho. p190RhoGAP has been shown to regulate axonal and dendritic extension and stability (Brouns et al., 2001; Billuart et al., 2001). Arg phosphorylation of p190RhoGAP peaks between 10 and 21 days postnatally, a period of extensive dendrite elaboration in the mouse cortex. We hypothesize that deficient phosphorylation of p190RhoGAP, may contribute to the reduced dendrite complexity of arg and/or abl mutant cortical neurons. Our second Aim will be to examine the requirement for p190RhoGAP in Abl/Arg-dependent control of cortical pyramidal neuron morphogenesis in vivo.