dab2ip regulates neuronal migration and neurite outgrowth in the developing neocortexdab2ip调节神经元迁移和神经突发展中大脑皮层的产物.pdf

Dab2ip Regulates Neuronal Migration and Neurite Outgrowth in the Developing Neocortex 1,2 3 4 1,2 Gum Hwa Lee , Sun Hong Kim , Ramin Homayouni , Gabriella D’Arcangelo * 1 Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America, 2 Graduate Program in Molecular Biosciences, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America, 3 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, United States of America, 4 Department of Biological Sciences, University of Memphis, Memphis, Tennessee, United States of America Abstract Dab2ip (DOC-2/DAB2 interacting protein) is a member of the Ras GTPase-activating protein (GAP) family that has been previously shown to function as a tumor suppressor in several systems. Dab2ip is also highly expressed in the brain where it interacts with Dab1, a key mediator of the Reelin pathway that controls several aspects of brain development and function. We found that Dab2ip is highly expressed in the developing cerebral cortex, but that mutations in the Reelin signaling pathway do not affect its expression. To determine whether Dab2ip plays a role in brain development, we knocked down or over expressed it in neuronal progenitor cells of the embryonic mouse neocortex using in utero electroporation. Dab2ip down-regulation severely disrupts neuronal migration, affecting preferentially late-born principal cortical neurons. Dab2ip overexpression also leads to migration defects. Structure-function experiments in vivo further show that both PH and GRD domains of Dab2ip are important for neuronal migration. A detailed an