Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biochemistry

Supervisor

Dr. Nathalie Berube

Abstract

Emerging evidence implicates the regulation of higher-order chromatin structure in brain development, maturation, and function. Human mutations in two important regulators of chromatin structure, ATRX and CTCF, cause microcephaly and intellectual disability and have been identified in several cancers, suggesting an important role for these proteins in the developing brain and to suppress tumorigenesis. This thesis demonstrates that chromatin structure is critical to the differentiation and survival of neural progenitor cells, and explores the mechanisms of ATRX and CTCF function in brain development. The first chapter identifies that Atrx deficiency induces replicative DNA damage at telomeres and pericentromeric heterochromatin, and the mutant mice display signs of premature aging, providing novel evidence that genetic damage restricted to the central nervous system can result in systemic defects that resemble aging. The second chapter demonstrates that the genome organizer CTCF is required for neural progenitor survival and to maintain the correct balance between proliferative and differentiative divisions in the mouse neocortex. The third chapter investigates the mechanism underlying p53- and PUMA-dependent apoptosis in Ctcf-null neural progenitor cells, focusing on a role for the protein in preventing replicative stress-induced apoptosis. Together, the findings presented here indicate that chromatin architectural proteins, such as ATRX and CTCF, are required for genomic stability to promote neural progenitor cell survival and support correct brain development.


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