The dashed circle outlines the telencephalon, which is visibly reduced in size in the embryos compared to littermate controls. normal development and function of the CNS. Whereas CTCF function has been studied extensively in cell culture systems, its function in an context remains to be completely resolved (Ohlsson et al., 2010). Ubiquitous deletion of CTCF in the mouse leads to lethality before embryonic day 3.5 (E3.5), suggesting that it is essential for early developmental processes (Fedoriw et al., 2004; Heath et al., 2008; Moore et al., 2012). Conditional deletion of in specific tissues causes either reduced proliferation or apoptotic cell death, depending on the tissue targeted for recombination. For example, deletion of in thymocytes resulted in increased and expression and cell cycle arrest, whereas reduced CTCF in mouse oocytes induced meiotic and mitotic defects and apoptotic cell death before the blastocyst stage (Fedoriw et al., 2004; Heath et al., 2008; Wan et al., 2008). Deletion of in the developing limb bud resulted in massive apoptosis and near-complete loss of limb structures, accompanied by increased p53 upregulated modulator of apoptosis (PUMA), a known activator of caspase-mediated apoptosis (Nakano and Vousden, 2001; Yu et al., 2001; Soshnikova et al., 2010). In human cancer cells, CTCF binds to the gene, and its depletion results in Piperazine citrate increased transcript and rapid apoptosis, indicating that transcription can be directly influenced by the presence or absence of CTCF (Gomes and Espinosa, 2010a,b). Given the deleterious effects of mutations in the human CNS, we specifically inactivated in the developing mouse brain. CTCF loss of function using two different driver lines in mice brought on apoptosis in dividing neuroprogenitor cells (NPCs) of the forebrain. Despite prevention of apoptosis by deletion, rescued double-null apical and outer radial glia (oRG) progenitors exhibited decreased proliferative capacity. Furthermore, loss of CTCF caused premature Rabbit polyclonal to ALS2 neurogenesis, resulting in depletion of the progenitor pool and a microcephaly phenotype at birth. These findings highlight the complexity of CTCF activities during neurogenesis. Materials and Methods Mouse husbandry and genotyping. Mice were exposed to 12 h light/dark cycles and fed tap water and regular chow mice, in which sites flank exons 3C12, have been described previously (Heath et al., 2008). Mice conditionally deficient in CTCF were generated by crossing knock-in male mice (129/sv background) or with heterozygous male mice (C57BL/6 background; Hbert and McConnell, 2000; Brub et al., 2005). To account for decreased expression due Piperazine citrate to knock-in Piperazine citrate of the Cre recombinase gene, driver line, mice were crossed with or genotyping WTgenotyping KOexpressionexpressionCBSCBS1CBS2CBSp53BSvalues were generated using Student’s test (unpaired, two-tailed) to compare between two impartial data sets. Genotype ratios (Figs. 1results in a massive increase in apoptosis. embryos at E13.5. (Please note limbs were taken for genotyping). embryos. embryos at E11.5. The dashed circle outlines the telencephalon, which is visibly reduced in size in the embryos compared to littermate controls. embryos. cortical neuroepithelium is usually shown. = 3). cortical neuroepithelium at E11.5. = 3). cortical neuroepithelium. Error bars represent the SEM. Original magnification: coronal forebrain sections. coronal forebrain sections. = 3). AC3+ cells were counted and expressed per unit area (square millimeter). basal ganglia. at 4 DIV. Het, brain. (conditional knock-out), and = 3). = 3). = 3). Data were analyzed by a one-way ANOVA followed by Dunnett’s multiple comparisons test to determine which means were significantly different from the control. No significant difference in cell viability was found at.
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