Abstract
In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actin Cytoskeleton / metabolism*
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Actin Cytoskeleton / ultrastructure
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Actin Depolymerizing Factors
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Animals
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Cell Differentiation / genetics*
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Cells, Cultured
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Conditioning, Psychological / physiology
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Cytoskeleton / metabolism
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Cytoskeleton / pathology
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Cytoskeleton / ultrastructure
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DNA-Binding Proteins / deficiency*
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DNA-Binding Proteins / genetics
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Dendrites / metabolism
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Dendrites / pathology*
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Dendrites / ultrastructure
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Excitatory Postsynaptic Potentials / genetics
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Fear / physiology
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Female
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Hippocampus / abnormalities*
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Hippocampus / growth & development
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Hippocampus / pathology
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Lim Kinases
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Long-Term Potentiation / genetics*
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Male
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Maze Learning / physiology
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Mice
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Mice, Knockout
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Microfilament Proteins / metabolism*
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Microtubule-Associated Proteins / metabolism
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Motor Activity / genetics
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Mutation / physiology
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Nervous System Malformations / genetics
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Nervous System Malformations / metabolism
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Nervous System Malformations / pathology
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Neural Inhibition / genetics
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Protein Kinases
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Up-Regulation / genetics
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Williams Syndrome / genetics
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Williams Syndrome / metabolism
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Williams Syndrome / pathology
Substances
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Actin Depolymerizing Factors
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DNA-Binding Proteins
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Microfilament Proteins
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Microtubule-Associated Proteins
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Protein Kinases
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Lim Kinases
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Limk1 protein, mouse
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Protein Serine-Threonine Kinases