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rdf:type |
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lifeskim:mentions |
umls-concept:C0006104,
umls-concept:C0025914,
umls-concept:C0026809,
umls-concept:C0205161,
umls-concept:C0248868,
umls-concept:C0332281,
umls-concept:C0332437,
umls-concept:C0441655,
umls-concept:C0596988,
umls-concept:C0769224,
umls-concept:C0872341,
umls-concept:C1412697
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pubmed:issue |
1
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pubmed:dateCreated |
2011-1-6
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pubmed:abstractText |
In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including ?-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX(?E2) mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX(?E2) mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX(?E2) mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX(?E2) mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX(?E2) mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX(?E2) mice may contribute to mental retardation syndromes seen in human patients.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ATRX protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Benzylamines,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium-Calmodulin-Dependent...,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Helicases,
http://linkedlifedata.com/resource/pubmed/chemical/Green Fluorescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Guanine Nucleotide Exchange Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Isoquinolines,
http://linkedlifedata.com/resource/pubmed/chemical/KN 93,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphopyruvate Hydratase,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 2,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides,
http://linkedlifedata.com/resource/pubmed/chemical/Tiam1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/kalirin protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/lucifer yellow
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1529-2401
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
5
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pubmed:volume |
31
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
346-58
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pubmed:meshHeading |
pubmed-meshheading:21209221-Adaptation, Ocular,
pubmed-meshheading:21209221-Analysis of Variance,
pubmed-meshheading:21209221-Animals,
pubmed-meshheading:21209221-Animals, Newborn,
pubmed-meshheading:21209221-Astrocytes,
pubmed-meshheading:21209221-Benzylamines,
pubmed-meshheading:21209221-Calcium-Calmodulin-Dependent Protein Kinase Type 2,
pubmed-meshheading:21209221-Cell Count,
pubmed-meshheading:21209221-Cells, Cultured,
pubmed-meshheading:21209221-Cognition Disorders,
pubmed-meshheading:21209221-Conditioning, Classical,
pubmed-meshheading:21209221-DNA Helicases,
pubmed-meshheading:21209221-Dendritic Spines,
pubmed-meshheading:21209221-Disease Models, Animal,
pubmed-meshheading:21209221-Exons,
pubmed-meshheading:21209221-Exploratory Behavior,
pubmed-meshheading:21209221-Fear,
pubmed-meshheading:21209221-Gene Expression Regulation,
pubmed-meshheading:21209221-Green Fluorescent Proteins,
pubmed-meshheading:21209221-Guanine Nucleotide Exchange Factors,
pubmed-meshheading:21209221-Humans,
pubmed-meshheading:21209221-Immunoprecipitation,
pubmed-meshheading:21209221-Isoquinolines,
pubmed-meshheading:21209221-Learning Disorders,
pubmed-meshheading:21209221-Maze Learning,
pubmed-meshheading:21209221-Mice,
pubmed-meshheading:21209221-Mice, Transgenic,
pubmed-meshheading:21209221-Motor Activity,
pubmed-meshheading:21209221-Mutation,
pubmed-meshheading:21209221-Neurons,
pubmed-meshheading:21209221-Nuclear Proteins,
pubmed-meshheading:21209221-Phosphopyruvate Hydratase,
pubmed-meshheading:21209221-Phosphorylation,
pubmed-meshheading:21209221-Prefrontal Cortex,
pubmed-meshheading:21209221-Protein Kinase Inhibitors,
pubmed-meshheading:21209221-Protein Phosphatase 1,
pubmed-meshheading:21209221-Protein Phosphatase 2,
pubmed-meshheading:21209221-RNA, Messenger,
pubmed-meshheading:21209221-Sulfonamides
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pubmed:year |
2011
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pubmed:articleTitle |
Aberrant calcium/calmodulin-dependent protein kinase II (CaMKII) activity is associated with abnormal dendritic spine morphology in the ATRX mutant mouse brain.
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pubmed:affiliation |
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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