Dual Effect of CTCF Loss on Neuroprogenitor Differentiation and Survival

• DOI: 10.1523/jneurosci.3769-13.2014
• Publication Date: 2014-02-19T17:41:24Z
• Authors: L. Ashley Watson; Xu Wang; Adrienne Elbert; Kristin D. Kernohan; Niels Galjart; Nathalie G. Bérubé
• Keywords: CTCF; Puma; Forebrain

An increasing number of proteins involved in genome organization have been implicated neurodevelopmental disorders, highlighting the importance chromatin architecture developing CNS. The CCCTC-binding factor (CTCF) is a zinc finger DNA binding protein higher-order organization, and mutations human CTCF gene cause an intellectual disability syndrome associated with microcephaly. However, information on function vivo brain lacking. To address this gap, we conditionally inactivated Ctcf at early stages mouse development. Cre-mediated deletion telencephalon anterior retina embryonic day 8.5 triggered upregulation p53 effector PUMA (p53 upregulated modulator apoptosis), resulting massive apoptosis profound ablation telencephalic structures. Inactivation several days later E11 also resulted increased apoptotic cell death, -null forebrain was hypocellular disorganized birth. Although both Puma efficiently rescued progenitor apoptosis, it failed to improve neonatal hypocellularity due decreased proliferative capacity apical outer radial glia cells. This exacerbated by independent effect loss that depletion pool premature neurogenesis earlier Our findings demonstrate activities are required for two distinct events cortex formation: first, correctly regulate balance between neuroprogenitor proliferation differentiation, second, survival cells, providing new clues regarding contributions microcephaly/intellectual pathologies.