WIP modulates dendritic spine actin cytoskeleton by transcriptional control of lipid metabolic enzymes.
We identify Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) as a novel component of neuronal synapses whose absence increases dendritic spine size and filamentous actin levels in an N-WASP/Arp2/3-independent, RhoA/ROCK/profilinIIa-dependent manner. These effects depend on the reduction of membrane sphingomyelin (SM) due to transcriptional upregulation of neutral sphingomyelinase (NSM) through active RhoA; this enhances RhoA binding to the membrane, raft partitioning and activation in steady state but prevents RhoA changes in response to stimulus. Inhibition of NSM or SM addition reverses RhoA, filamentous actin and functional anomalies in synapses lacking WIP. Our findings characterize WIP as a link between membrane lipid composition and actin cytoskeleton at dendritic spines. They also contribute to explain cognitive deficits shared by individuals bearing mutations in the region assigned to the gene encoding for WIP.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Centro Nacional de Biotecnología (CNB-CSIC), Madrid 28049, Spain.
Ana
A
Franco-Villanueva
Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Centro Nacional de Biotecnología (CNB-CSIC), Madrid 28049, Spain.
Estefanía
E
Fernández-López
Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and.
Enrique
E
Gabandé-Rodríguez
Centro Nacional de Biotecnología (CNB-CSIC), Madrid 28049, Spain.
Inmaculada
I
Bañón-Rodríguez
Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and.
Jose Antonio
JA
Esteban
Centro Nacional de Biotecnología (CNB-CSIC), Madrid 28049, Spain ianton@cnb.csic.es dledesma@cbm.csic.es.
Inés M
IM
Antón
Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and ianton@cnb.csic.es dledesma@cbm.csic.es.
María Dolores
MD
Ledesma
D008841:Actin Cytoskeleton / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D003598:Cytoskeletal Proteins; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D061251:Primary Cell Culture; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D013109:Sphingomyelins; C495768:Was protein, mouse; C495772:Wasl protein, mouse; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D051300:Wiskott-Aldrich Syndrome Protein Family; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D013108:Sphingomyelin Phosphodiesterase; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein