Research Paper Volume 10, Issue 6 pp 1223—1238

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

Megan E. Rowland 1, 2, , Yan Jiang 1, 2, , Frank Beier 2, 3, 4, , Nathalie G. Bérubé 1, 2, ,

  • 1 Departments of Paediatrics and Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
  • 2 Children’s Health Research Institute, London, ON, Canada
  • 3 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
  • 4 Western Bone and Joint Institute, Western University, London, ON, Canada

received: January 24, 2018 ; accepted: May 30, 2018 ; published: June 7, 2018 ;
How to Cite

Copyright: Rowland et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


ATRX is an ATP-dependent chromatin remodeler required for the maintenance of genomic integrity. We previously reported that conditional Atrx 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 Atrx 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 Igf1 and several other thyroid hormone responsive genes failing to recover normal expression levels. These findings hinted at Cre-mediated Atrx inactivation in the liver of Atrx Foxg1cre mice, which we confirmed. We conclude that the phenotypes observed in the Atrx Foxg1cre mice can be explained in part by a role of ATRX in the liver to promote T4-mediated Igf1 expression, thus explaining the inefficacy of T4 therapy observed in this study.


IGF-1: insulin-like growth factor 1; T4: thyroxine; ATRX: α-Thalassemia/mental retardation X-linked; Swi/Snf: Switch/Sucrose non-fermenting; ADD: ATRX-DNTM3-DNTM3L; NPC: neuroprogenitor cell; T3: triiodothyronine; Thr: thyroid hormone receptor; Dio3: deiodinase 3; Igf1r: Igf1 receptor; Igf2r: Igf2 receptor; IGFBP: insulin-like growth factor binding protein; IGFALS: insulin-like growth factor acid labile subunit; TBG: thyroxine binding globulin; Thrβ: Thyroid hormone receptor β; GFP: green fluorescent protein; NER: nucleotide excision repair; ICR: imprinting control region.