The guanine nucleotide exchange factor (GEF) Asef2 promotes dendritic spine formation via Rac activation and spinophilin-dependent targeting.
Dendritic spines are actin-rich protrusions that establish excitatory synaptic contacts with surrounding neurons. Reorganization of the actin cytoskeleton is critical for the development and plasticity of dendritic spines, which is the basis for learning and memory. Rho family GTPases are emerging as important modulators of spines and synapses, predominantly through their ability to regulate actin dynamics. Much less is known, however, about the function of guanine nucleotide exchange factors (GEFs), which activate these GTPases, in spine and synapse development. In this study we show that the Rho family GEF Asef2 is found at synaptic sites, where it promotes dendritic spine and synapse formation. Knockdown of endogenous Asef2 with shRNAs impairs spine and synapse formation, whereas exogenous expression of Asef2 causes an increase in spine and synapse density. This effect of Asef2 on spines and synapses is abrogated by expression of GEF activity-deficient Asef2 mutants or by knockdown of Rac, suggesting that Asef2-Rac signaling mediates spine development. Because Asef2 interacts with the F-actin-binding protein spinophilin, which localizes to spines, we investigated the role of spinophilin in Asef2-promoted spine formation. Spinophilin recruits Asef2 to spines, and knockdown of spinophilin hinders spine and synapse formation in Asef2-expressing neurons. Furthermore, inhibition of N-methyl-d-aspartate receptor (NMDA) activity blocks spinophilin-mediated localization of Asef2 to spines. These results collectively point to spinophilin-Asef2-Rac signaling as a novel mechanism for the development of dendritic spines and synapses.
From the Department of Biological Sciences and the Kennedy Center for Research on Human Development and.
J Corey
JC
Evans
From the Department of Biological Sciences and the Kennedy Center for Research on Human Development and.
Cristina M
CM
Robinson
From the Department of Biological Sciences and the Kennedy Center for Research on Human Development and.
Mingjian
M
Shi
From the Department of Biological Sciences and the Kennedy Center for Research on Human Development and the Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37235 donna.webb@vanderbilt.edu.
Donna J
DJ
Webb
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000099273:Neurabins
D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D000099273:Neurabins
Dendrite; Guanine Nucleotide Exchange Factor (GEF); Neuron; Rac (Rac GTPase); Rho (Rho GTPase); Synapse