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[P210]: SNF2L‐mediated control of cell number in the developing brain
Author(s) -
Yip D.J.,
Maria A.,
Coulombe J.,
Rudnicki M.,
Picketts D.J.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.270
Subject(s) - library science , research program , medicine , family medicine , computer science , philosophy , epistemology
Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however knowledge of the role of these proteins in normal CNS development is limited. In Drosophila, ISWI is essential for development and the protein functions as the ATPhydrolysing component in several chromatin-remodeling complexes. The two mammalian ISWI orthologs, SNF2H and SNF2L are differentially expressed, suggesting that they possess distinct developmental roles. Prevalent expression of SNF2H occurs during neuroprogenitor proliferation while SNF2L transcripts have increased levels in maturing neurons. Here we use conditional Cre-loxP gene-targeting to inactivate the murine Snf2l gene in order to assess its role in neurodevelopment. Heterozygous females (Snf2l) were crossed to mice expressing Crerecombinase under the control of the GATA-1 promoter. SNF2Lnull male mice were viable and born at classic Mendelian ratios. These mice displayed no overt developmental or behavioral abnormalities; however, the loss of Snf2l resulted in a 2-fold increase in the brain weight to body weight ratio. This was accompanied by a concomitant increase in cell number in the hippocampus and cerebral cortex ranging from 0.5to 2-fold in the six distinct cortical layers and a 2-fold increase in all hippocampal strata. Moreover we observed a proportionate increase in BrdU staining of the ventricular and intermediate zones of day 15.5 embryonic cortices, coupled with an approximately 3fold increase in cells undergoing mitosis. These results suggest that the increased cell number within the adult brain arose from enhanced embryonic neuroprogenitor proliferation. Finally, loss of Snf2l protein was accompanied by an increase in Snf2h protein levels, suggesting that Snf2h can functionally compensate for the loss of Snf2l in the mutant mice. Taken together, our results indicate that a proper balance of Snf2h to Snf2l protein ratios is an important regulator of brain size and/or cell number.