Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span
L. Ashley Watson, … , Frank Beier, Nathalie G. Bérubé
L. Ashley Watson, … , Frank Beier, Nathalie G. Bérubé
Published April 8, 2013
Citation Information: J Clin Invest. 2013;123(5):2049-2063. https://doi.org/10.1172/JCI65634.
View: Text | PDF
Research Article Aging

Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span

Abstract

Human ATRX mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres and pericentromeric heterochromatin, which is exacerbated by loss of p53 and linked to ATM activation. ATRX-deficient neuroprogenitors exhibited higher incidence of telomere fusions and increased sensitivity to replication stress–inducing drugs. Treatment of Atrx-null neuroprogenitors with the G-quadruplex (G4) ligand telomestatin increased DNA damage, indicating that ATRX likely aids in the replication of telomeric G4-DNA structures. Unexpectedly, mutant mice displayed reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. We show that a subset of these defects can be attributed to loss of ATRX in the embryonic anterior pituitary that resulted in low circulating levels of thyroxine and IGF-1. Our findings suggest that loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary and causes tissue attrition and other systemic defects similar to those seen in aging.

Authors

L. Ashley Watson, Lauren A. Solomon, Jennifer Ruizhe Li, Yan Jiang, Matthew Edwards, Kazuo Shin-ya, Frank Beier, Nathalie G. Bérubé

×

Figure 4

Reduced growth and life span in mice lacking ATRX in the forebrain.

Options: View larger image (or click on image) Download as PowerPoint
Reduced growth and life span in mice lacking ATRX in the forebrain. (A) ...
(A) Kaplan-Meier survival curve of Cre+ control (n = 12) and cKO mice raised with (+sibs, n = 13) or without (–sibs, n = 11) siblings. Survival of cKO mice was significantly decreased compared with that of control mice (P = 0.0001). The survival of cKO mice was not significantly different whether they were raised with or without siblings (P = 0.4974). (B) Representative pictures of P17 control and cKO littermates, illustrating size difference of the mice. (C) Body weight (g) and length (cm) measurements of control (Cre–, n = 25; Cre+, n = 8) and cKO (n = 24) mice. No significant difference was observed between Cre– and Cre+ control mice. (D) Skeletal elements of control and cKO mice were stained with alizarin red and alcian blue. (E) Length measurements of P17 control and cKO skeletal elements. (n = 5). *P < 0.05.