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.
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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

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Figure 6

Endocrine defects and hypoglycemia in Atrx-cKO mice.

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Endocrine defects and hypoglycemia in Atrx-cKO mice. (A) Longitudinal ...
(A) Longitudinal growth of control and cKO tibia was measured after 7 days (d7) of ex vivo culture. Results are expressed as the ratio of length at d7 to that at d0. No difference in growth was detected between control and cKO mice (n = 3). Scale bar: 100 μm. (B) Serum and liver IGF-1 levels are decreased in cKO mice (n = 3). (C) Expression of several IGF-1 pathway genes is altered in cKO liver compared with controls (n = 3). Real-time data were normalized to Gapdh expression. (D) Circulating T4 levels are significantly decreased in P20 cKO mice compared with controls, while GH levels are only mildly affected (n = 3). (E) Thyroid hormone target genes exhibit decreased expression in the liver of P20 cKO mice compared with controls (n = 3). Real-time data were normalized to Gapdh expression. (F) Glucose levels are reduced in P20 cKO serum compared with controls (n = 5). Original magnification, ×50 (A). *P < 0.05.