Background: Mutations in genes whose products modify chromatin structure have been recognized as a cause of X-linked mental retardation (XLMR). These genes encode proteins that regulate DNA methylation (MeCP2), modify histones (RSK2 and JARID1C), and remodel nucleosomes through ATP hydrolysis (ATRX). Thus, genes encoding other chromatin modifying proteins should also be considered as disease candidate genes. In this work, we have characterized the SNF2L gene, encoding an ATP-dependent chromatin remodeling protein of the ISWI family, and sequenced the gene in patients from 12 XLMR families linked to
foetal environment can re-pattern development. We previously identified four microRNAs in foetal neural stem (NSC) and progenitor (NPC) cells, miR9, 21, 153 and 335, which were specifically suppressed by the neuroteratogen, ethanol [Sathyan et al., 2007, J. Neurosci. 27(32): 8546-8557]. Moreover, the sensitivity of these microRNAs collectively explained many of ethanol's effects on NSC renewal and maturation. We found that mir335 particularly, plays an important role in NSC/NPC survival and proliferation. MiR335 is coded within the MEST gene locus, which is implicated in the aetiology of the Russell-Silver syndrome, as well as in the spatial patterning of the emerging cerebral cortex. In situ hybridization and immuno-fluorescence analyses indicate that both mir335 and MEST localize to the apical cells of the fetal ventricular zone, further suggesting that the MEST/miR335 locus controls the proliferation and maturation of NSCs. To further study miR335's impact on NSC/ NPC maturation, we cultured foetal mouse neuroepithelial cells as non-adherent neurospheres. We used microarray approach to identify key genes targeted by miR-335. Our results indicate that 214 genes encompassing MAP Kinase, steroid biosynthesis and actin cytoskeleton reorganization pathways were significantly up-regulated following miR335 knockdown. Preliminary data indicates that FGF, which controls NSC renewal, also promotes the expression of miR335. These data collectively suggest that miR335 is an integral part of a complex signalling web that controls the growth and maturation of foetal NSCs. Its teratogen-sensitivity further supports the conclusion that microRNAs represent windows of vulnerability that render the developing foetus susceptible to environmental disrupters.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.