WRP AS A CANDIDATE MENTAL RETARDATION ASSOCIATED GENE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mental retardation (MR) affects 2-3% of the general population. It is increasingly clear that signaling to the actin cytoskeleton by Rho-GTPases plays a central role in the development of the CNS. Rho-GTPases (numbered at 22 genes) are regulated by a large number of Rho Guanine Nucleotide Exchange Factors (GEFs; 85 genes) and Rho GTPase Activating Proteins (GAPs; 70 genes). Recent studies have identified members of this pathway as potential genes affected in MR. One such MR gene is WAVE Associated Rac-GAP Protein (WRP), which we originally discovered as a neuronal GAP that binds the Rac effector protein, WAVE-1. WRP is a member of a family of four neuronal GAPs (WRP, WRP2, WRP3, and RhoGAP-C1) that are proposed to regulate axonal guidance, cortical migration, and development of dendritic spines. Aim: Test the in vivo function of WRP GAP family members WRP and WRP2 in regulating central nervous system development. We will test the possible role of WRP in MR by analyzing a new line of WRP null mice we have recently developed. In collaboration with the Duke Center for In Vivo Microscopy we will conduct morphometric analysis of brains from WRP null mice. Area measurements and shape analysis will be performed for a variety of brain structures compared to wildtype littermates similar to that recently conducted for the Reeler mouse model (Badea, A., et.al., Neuroimage 2007). This analysis will especially examine lateral ventricle volume since our preliminary data suggests these may be dilated in the WRP null mouse model. These data will complement parrallel studies of cultured neurons and histology to quantify the morphology and polarity of individual neurons. Behavioral studies of WRP null mice done in collaboration with Dr. William Wetsel will directly examine the role of WRP in cognitive functioning. A second line of knockout mice is currently being made for WRP2. This GAP protein is thought to regulate the laminar development of the cortex, possibly by regulating the actin dynamics of neurons during radial migration. Magnetic resonance microscopy will also be used the perform morphometric analysis of these mice, similar to the study outlined above. The combined results from the above study will have an important positive impact by furthering our understanding of the molecular, genetic, and developmental mechanisms that may be involved in mental retardation.