ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory.
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.
Grove
Matthew
M
Duke University Medical Center, Department of Pharmacology and Cancer Biology, Box 3813, Durham, NC 27710, USA.
Demyanenko
Galina
G
Echarri
Asier
A
Zipfel
Patricia A
PA
Quiroz
Marisol E
ME
Rodriguiz
Ramona M
RM
Playford
Martin
M
Martensen
Shelby A
SA
Robinson
Matthew R
MR
Wetsel
William C
WC
Maness
Patricia F
PF
Pendergast
Ann Marie
AM
D048868:Adaptor Proteins, Signal Transducing; D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D003712:Dendrites / Q000235:genetics; D049229:Dendritic Spines / Q000235:genetics*; D004285:Dogs; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007858:Learning; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics*; D019579:Neocortex / Q000166:cytology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
C490756:Abi2 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering