Inactivation of hepatic ATRX in Foxg1cre mice prevents reversal of aging-like phenotypes by thyroxine.

ATRX is an ATP-dependent chromatin remodeler required for the maintenance of genomic integrity. We previously reported that conditional ablation in the mouse embryonic forebrain and anterior pituitary using the Foxg1cre driver causes reduced health and lifespan. In these mice, premature aging-like phenotypes were accompanied by low circulating levels of insulin-like growth factor 1 (IGF-1) and thyroxine (T4), hormones that maintain stem cell pools and normal metabolic profiles, respectively. Based on emerging evidence that T4 stimulates expression of IGF-1 in pre-pubertal mice, we tested whether T4 supplementation in Foxg1cre mice could restore IGF-1 levels and ameliorate premature aging-like phenotypes. Despite restoration of normal serum T4 levels, we did not observe improvements in circulating IGF-1. In the liver, thyroid hormone target genes were differentially affected upon T4 treatment, with and several other thyroid hormone responsive genes failing to recover normal expression levels. These findings hinted at Cre-mediated inactivation in the liver of Foxg1cre mice, which we confirmed. We conclude that the phenotypes observed in the Foxg1cre mice can be explained in part by a role of ATRX in the liver to promote T4-mediated expression, thus explaining the inefficacy of T4 therapy observed in this study.