Abi2-Deficient Mice Exhibit Defective Cell Migration, Aberrant Dendritic Spine Morphogenesis, and Deficits in Learning and Memory

Abstract

The Abl-interactor (Abi) family of adaptor proteins has been linked to signaling pathways involving the Abl tyrosine kinases and the Rac GTPase. Abi proteins localize to sites of actin polymerization in protrusive membrane structures and regulate actin dynamics in vitro. Here we demonstrate that Abi2 modulates cell morphogenesis and migration in vivo. Homozygous deletion of murine abi2 produced abnormal phenotypes in the eye and brain, the tissues with the highest Abi2 expression. In the absence of Abi2, secondary lens fiber orientation and migration were defective in the eye, without detectable defects in proliferation, differentiation, or apoptosis. These phenotypes were consistent with the localization of Abi2 at adherens junctions in the developing lens and at nascent epithelial cell adherens junctions in vitro. Downregulation of Abi expression by RNA interference impaired adherens junction formation and correlated with downregulation of the Wave actin-nucleation promoting factor. Loss of Abi2 also resulted in cell migration defects in the neocortex and hippocampus, abnormal dendritic spine morphology and density, and severe deficits in short- and long-term memory. These findings support a role for Abi2 in the regulation of cytoskeletal dynamics at adherens junctions and dendritic spines, which is critical for intercellular connectivity, cell morphogenesis, and cognitive functions.

We thank Cheryl Bock at the DUMC Transgenic Mouse Facility for the generation of the Abi2 null mice. We are grateful to Philippe Soriano for advice in the preparation of the targeting construct and the kind gifts of the pPGKneobpAloxPGKDTA vector and the 129 Sv mouse genomic DNA library. We thank Frank Gertler for electroporation of the targeting construct into ES cells and Kevin D. Courtney for advice. We are grateful to Sam Zigler for the anti-MIP26 and anti-γ crystallin antibodies and Matthew Welch for the anti-p34 Arc antibody. We thank Guoping Feng, Michael Ehlers, Anthony-Samuel La Mantia, Vasanth Rao, Joseph Costello, and Gordon Klintworth for insightful suggestions and Anthony Means and Tso-Pang Yao for critical reading of the manuscript.

This work was supported in part by National Institutes of Health grants R01 CA70940 and GM62375 to A.M.P. and R01 HD35170 and NS26620 to P.F.M., by grant 12-FY99-468 from the March of Dimes Birth Defects Foundation, and by a grant from the National Alliance for Research on Schizophrenia and Depression to W.C.W.