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 stressinducing 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.

Although peroxisome proliferator activated receptor (PPAR)γ remains a critical regulator of preadipocyte differentiation, new roles have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity and atherosclerosis. Despite the demonstration of PPARγ expression in chondrocytes, its role and the pathways affecting its expression and activity in chondrocytes remain largely unknown. We investigated the effects of PPARγ activation on chondrocyte differentiation and its participation in chondrocyte lipid metabolism. PPARγ2 expression is highly regulated during chondrocyte differentiation in vivo and in vitro PPARγ activation with troglitazone resulted in increased Indian hedgehog expression and reduced collagen X expression, confirming previously described roles in the inhibition of differentiation. However, the major effect of PPARγ2 in chondrocytes appears to be on lipid metabolism. During differentiation chondrocytes increase expression of the lipid-associated metabolizing protein, Lpl, which is accompanied by increased gene expression of PPARγ. PPARγ expression is suppressed by p38 activity, but requires GSK-3 activity. Furthermore, Lpl expression is regulated by p38 and GSK-3 signalling. This is the first study demonstrating a relationship between PPARγ2 expression and chondrocyte lipid metabolism and its regulation by p38 and GSK-3 signalling.