Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 16, Pages 4383-4395Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu155
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Funding
- Ministerio Espanol de Ciencia e Innovacion [SAF2011-24550, CSD2010-00045, BFU2010-21374/BMC]
- Fundacion Ramon Areces
- JAE-PreDoc (Spanish National Research Council)
- FPU (Ministerio Espanol de Ciencia e Innovacion)
- Fundacion Severo Ochoa
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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.
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