Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biochemistry

Supervisor

Dr. Nathalie Berube

Abstract

Mutations in the ATRX gene cause alpha thalassemia mental retardation X-linked syndrome (ATR-X). Individuals with ATR-X syndrome show a broad range of developmental abnormalities including severe cognitive, behavioural, and learning deficits, seizures, and microcephaly, indicating that ATRX is essential for normal development of the central nervous system. Conditional inactivation of Atrx in the developing mouse forebrain leads to a reduction in cerebral cortical size, elevated levels of p53-dependent neuronal apoptosis, and dysgenesis of certain subcortical structures, including the hippocampus and dentate gyrus, confirming a requirement for Atrx in mammalian brain development. The mammalian ATRX gene encodes a member of the Snf2 type family of chromatin remodeling proteins. Although ATRX can function as a transcriptional regulator, it is highly enriched at pericentromeric heterochromatin, a domain of constitutive heterochromatin important for proper centromere function during mitotic cell division. To investigate the role of ATRX in mitotic cell division, RNA interference was used to specifically depleted ATRX expression in a human cancer cell line. Live cell imaging of the ATRX depleted cells revealed mitotic dysfunction, including chromosome congression and alignment defects and chromosome bridging, accompanied by a reduction of centromeric sister chromatid cohesion. ATRX depleted cells also displayed elevated levels of cytokinetic failure and multinucleation, but normal cytokinetic midbody structure. Mitotic regulation of neuronal progenitor proliferation and differentiation is a primary mechanism of cerebral cortical neurogenesis. Mitotic neuronal progenitor cells from the embryonic Atrx-null mouse forebrain display mitotic dysfunction in vitro and in vivo. Furthermore, apical neuronal progenitors of the Atrx-null forebrain display a disruption in the balance of symmetric to asymmetric cell divisions, leading to an altered compliment of differentiated neurons in the postnatal cortex. Taken together, this data present a novel role for the chromatin remodeling protein ATRX in mitotic cell division and cortical neurogenesis.


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Cell Biology Commons

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