Expression of genes encoding neuropeptides, receptors and enzymes in the brain, with emphasis on the hypothalamus, are being studied. We successfully created a knock-out of the vasopressin 1b receptor (V1bR) gene in mice through homologous recombination. These mice are growing normally and we are studying them using a variety of different physiological and behavioral challenges. They are not as aggressive as their wildtype littermates, which presents the opportunity to examine the neurological basis of aggression. They also show mild reduction in social recognition. We also cloned the rat ARHGAP4, a member of the Rho GTPase activating protein family, and demonstrated its close linkage to the vasopressin 2 receptor gene. In vitro, recombinant ARHGAP4 stimulated the GTPase activity of three members of Rho GTPases, Rac1, Cdc42 and RhoA. ARHGAP4 mRNA expression was observed in multiple tissues with marked expression throughout the developing and adult nervous systems, including in the stratum lucidem in the CA3 area of the hippocampus, neuronal fibers in the ventral region of the brainstem and striatum, and in the cerebellar granule cells. Subcellularly, endogenous ARHGAP4 expression localized to the Golgi complex and could redistribute to the microtubules, for example during mitosis. In addition, distinct protein expression was observed in the tips of differentiating neurites of PC12 cells. ARHGAP4 potentially possesses specialized activity in regulating members of the Rho GTPase family in specific cellular compartments of the nervous system.
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