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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.

SUBMITTER: Watson LA

PROVIDER: S-EPMC3635723 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Watson L Ashley LA Solomon Lauren A LA Li Jennifer Ruizhe JR Jiang Yan Y Edwards Matthew M Shin-ya Kazuo K Beier Frank F Bérubé Nathalie G NG

The Journal of clinical investigation 20130408 5

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-quadrupl ...[more]

PMID: 23563309

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Project description:Simple Summary ATRX and DAXX mutations occur in 30–40% of pancreatic neuroendocrine tumours (PanNETs), and there are no reports in the literature of any genetically engineered mouse model (GEMM) evaluating the effect of Atrx disruption as a putative driver event on PanNET initiation. We created a novel GEMM with Atrx conditional disruption in β cells. We observed that this genetic alteration, per se, was not tumourigenic, but we reported novel roles of Atrx on endocrine function, which resulted in dysglycaemia and the exacerbation of inflammageing (increased pancreatic inflammation and hepatic steatosis). Abstract ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.

Dataset Information

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

Publications

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

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