Nuclear architecture changes as cell fate specification occurs. During development, chromatin domains adopt distinct spatial distributions, with repressed domains directed to the nuclear periphery. Such positioning depends on the extensive protein network that lines the inner nuclear envelope, known as the nuclear lamina. Included in this network are the LAP2-emerin-MAN1-domain (LEM-D) proteins. This family of proteins binds lamins and tethers repressive chromatin to the nuclear periphery. The importance of the human family of LEM-D proteins is underscored by the fact that loss of individual proteins causes progressive, tissue-restricted diseases, including muscular dystrophy, cardiomyopathy and bone density disorders. Mechanisms by which LEM-D proteins contribute to these diseases are poorly understood. To understand the function of LEM-D proteins, our laboratory has investigated three members of the Drosophila family, Otefin, Bocksbeutel and dMAN1. Genetic studies revealed that each protein has unique and over-lapping functions during development, with loss of individual proteins causing age-enhanced phenotypes. As an example of these development contributions, the LEM-D protein Otefin is uniquely required for oogenesis. Loss of Otefin causes premature death of adult germline stem cells (GSCs) wherein mutant GSCs display features of aging, including altered nuclear structure and chromatin organization. GSC death results from activation of the DNA damage signaling kinases ATR and Chk2. Surprisingly, ATR/Chk2 activation occurs without evidence of DNA damage or transposon transcription. Together, these findings reveal that GSCs have a novel survival checkpoint that depends on nuclear architecture. Our studies suggest that human pathologies result from progressive dysfunction of adult stem cell populations that lead to defects in tissue homeostasis.