Electronic Thesis and Dissertation Repository

Thyroxine-Dependent and -Independent Effects on Premature Aging and Myelination in ATRX Mutant Mice

Megan E. Rowland, The University of Western Ontario

Abstract

ATRX is an ATP-dependent chromatin remodeler required to safeguard genomic integrity. Conditional deletion of Atrx in the mouse embryonic forebrain and anterior pituitary in AtrxFoxg1Cre mice phenocopies mouse models of progeria which display increased DNA damage, coupled with reduced lifespan, growth and subcutaneous fat. These mice also have severely low circulating levels of insulin like growth factor 1 (IGF-1) and (T4) which have been reported in models of premature aging. Based on evidence that Igf1 is activated by the ligand-bound thyroid hormone receptor, I tested whether T4 supplementation could restore IGF-1 levels and ameliorate premature aging phenotypes in AtrxFoxG1Cre mice. However, restoration of normal serum T4 levels failed to rescue circulating IGF-1 levels, growth defects or reduced lifespan. This could be explained in part by an unexpected deletion of ATRX in hepatocytes where ATRX promotes thyroid hormone receptor mediated Igf1 expression. In the second half of this thesis, I demonstrated that AtrxFoxG1Cre mice are also characterized by nervous system hypomyelination, another aging-related phenotype. Myelin is produced by oligodendrocytes and ensures rapid propagation of action potentials necessary for higher cognitive functioning. Systemic thyroxine supplementation improved myelin levels by promoting oligodendrocyte differentiation. However, myelin restoration was incomplete, as the number of oligodendrocyte precursor cells (OPCs) was still diminished, pointing to additional roles of ATRX in the generation or maintenance of these cells. Using directed inactivation of Atrx in postnatal OPCs or neurons, I established that ablation of ATRX in the former, but not the latter, results in hypomyelination. ATRX-null OPCs displayed a more plastic state in vitro and in vivo, allowing a shift from a strict oligodendrocyte differentiation program toward ectopic astrogliogenesis, ultimately leading to hypomyelination. Mechanistically, I provide evidence that ATRX associates with the histone deacetylase HDAC3 in OPCs to promote transcription of the Olig2 fate specification gene. Collectively this study identified thyroxine-dependent and -independent effects of Atrx gene activation on premature aging-like phenotypes in mice.