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Phosphoprotein associated with glycosphingolipid-enriched microdomains differentially modulates SRC kinase activity in brain maturation.

PloS one | Sep 14, 2011

Src family kinases (SFK) control multiple processes during brain development and function. We show here that the phosphoprotein associated with glycosphigolipid-enriched microdomains (PAG)/Csk binding protein (Cbp) modulates SFK activity in the brain. The timing and localization of PAG expression overlap with Fyn and Src, both of which we find associated to PAG. We demonstrate in newborn (P1) mice that PAG negatively regulates Src family kinases (SFK). P1 Pag1(-/-) mouse brains show decreased recruitment of Csk into lipid rafts, reduced phosphorylation of the inhibitory tyrosines within SFKs, and an increase in SFK activity of >/ = 50%. While in brain of P1 mice, PAG and Csk are highly and ubiquitously expressed, little Csk is found in adult brain suggesting altered modes of SFK regulation. In adult brain Pag1-deficiency has no effect upon Csk-distribution or inhibitory tyrosine phosphorylation, but kinase activity is now reduced (-20-30%), pointing to the development of a compensatory mechanism that may involve PSD93. The distribution of the Csk-homologous kinase CHK is not altered. Importantly, since the activities of Fyn and Src are decreased in adult Pag1(-/-) mice, thus presenting the reversed phenotype of P1, this provides the first in vivo evidence for a Csk-independent positive regulatory function for PAG in the brain.

Pubmed ID: 21915273 RIS Download

Mesh terms: Animals | Animals, Newborn | Blotting, Western | Brain | Glycosphingolipids | Immunoprecipitation | In Situ Hybridization | Membrane Proteins | Mice | Mice, Knockout | Phosphoproteins | Reverse Transcriptase Polymerase Chain Reaction | src-Family Kinases

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Allen Institute for Brain Science

Independent 501(c)(3) nonprofit medical research organization dedicated to accelerating the understanding of how the human brain works. Utilizing the mouse model system, a multidisciplinary group of neuroscientists, molecular biologists, informaticists, engineers, mathematicians, statisticians, and computational biologists have joined together to investigate expression of 20,000 genes in the adult mouse brain and to map gene expression to a cellular level beyond neuroanatomic boundaries. The data generated from this joint effort is contained in the publicly available Allen Brain Atlas application. Molecular approaches to understanding the functional organization of the brain promise new insights into the relationships between genes, brain, behavior and disease. To facilitate such insights, the Allen Institute produces large-scale projects and makes the resulting data and tools freely available online to scientists worldwide. These open resources, all available at www.brain-map.org, are intended to foster scientific discovery and collaboration. Atlases: Allen Developing Mouse Brain Atlas: A map of gene expression in the developing mouse brain. Building on the Allen Mouse Brain Atlas, this atlas reveals gene expression patterns from embryonic through postnatal stages to provide information about both spatial and temporal regulation of gene expression. Allen Spinal Cord Atlas: A genome-wide map of gene expression throughout the adult and juvenile mouse spinal cord. The Atlas was made possible through the generous support of a diverse consortium of funders, representing disease organizations, foundations, and corporate and private donors. Allen Mouse Brain Atlas (formerly Allen Brain Atlas): A genome-wide, three-dimensional map of gene expression in the adult mouse brain. Similar in scale to the Human Genome Project, the Atlas reveals the expression patterns of approximately 20,000 genes throughout the entire adult mouse brain down to the cellular level. The Allen Institutes inaugural project, the Atlas was completed in 2006. Studies: Mouse Diversity Study: Characterization of gene expression in the brain across genetic backgrounds and sex. Expanding on the Allen Mouse Brain Atlas, this resource includes data for 49 pharmaceutical drug target genes and a selected set of additional genes across seven mouse strains and in female mice. Transgenic Mouse Study: Comprehensive characterization of the expression patterns of genetically-controlled markers or tool genes in the brains of transgenic mice. Providing standardized, detailed, anatomical profiling of transgene expression throughout the brain, this dataset is intended to reveal the potential of each transgenic mouse line and help researchers choose the appropriate tools for their studies. Human Cortex Study: A collection of gene expression data in the adult human neocortex. Providing data for several categories of genes across different cortical regions and human individuals, including control and schizophrenic cases, the dataset has the potential to enable exploration of variability in cortical gene expression across different ages, between genders across different regions of the cortex and in schizophrenia. Sleep Study: A comprehensive collection of gene expression data in the mouse brain for five different conditions of sleep and wakefulness. Generated in collaboration with SRI International, this unique dataset is intended to help sleep researchers advance understanding of sleep deprivation and the dynamic changes underlying sleep/wake cycles. The sleep study was funded by an award from the U.S. Department of Defense.

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