Dual Effect of CTCF Loss on Neuroprogenitor Differentiation and Survival
570
CCCTC-Binding Factor
Chromatin Immunoprecipitation
Antimetabolites
Cell Survival
Neurogenesis
610
Fluorescent Antibody Technique
Apoptosis
Mouse model
Nestin
Mice
03 medical and health sciences
Neural Stem Cells
Image Processing, Computer-Assisted
Animals
Mice, Knockout
0303 health sciences
Cell Death
EMC MGC-02-13-02
Brain
Cell Differentiation
Exons
CTCF
Genes, p53
Bromodeoxyuridine
Differentiation
Female
Puma
Apoptosis Regulatory Proteins
DOI:
10.1523/jneurosci.3769-13.2014
Publication Date:
2014-02-19T17:41:24Z
AUTHORS (6)
ABSTRACT
An increasing number of proteins involved in genome organization have been implicated in neurodevelopmental disorders, highlighting the importance of chromatin architecture in the developing CNS. The CCCTC-binding factor (CTCF) is a zinc finger DNA binding protein involved in higher-order chromatin organization, and mutations in the humanCTCFgene cause an intellectual disability syndrome associated with microcephaly. However, information on CTCF functionin vivoin the developing brain is lacking. To address this gap, we conditionally inactivated theCtcfgene at early stages of mouse brain development. Cre-mediatedCtcfdeletion in the telencephalon and anterior retina at embryonic day 8.5 triggered upregulation of the p53 effector PUMA (p53 upregulated modulator of apoptosis), resulting in massive apoptosis and profound ablation of telencephalic structures. Inactivation ofCtcfseveral days later at E11 also resulted in PUMA upregulation and increased apoptotic cell death, and theCtcf-null forebrain was hypocellular and disorganized at birth. Although deletion of bothCtcfandPumain the embryonic brain efficiently rescuedCtcf-null progenitor cell apoptosis, it failed to improve neonatal hypocellularity due to decreased proliferative capacity of rescued apical and outer radial glia progenitor cells. This was exacerbated by an independent effect of CTCF loss that resulted in depletion of the progenitor pool due to premature neurogenesis earlier in development. Our findings demonstrate that CTCF activities are required for two distinct events in early cortex formation: first, to correctly regulate the balance between neuroprogenitor cell proliferation and differentiation, and second, for the survival of neuroprogenitor cells, providing new clues regarding the contributions of CTCF in microcephaly/intellectual disability syndrome pathologies.
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