Résumé :
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Lamina-Associated Polypeptide 2 (LAP2) alpha belongs to a family of nucleoskeletal proteins that bind to chromatin and lamins. While the majority of lamins forms a scaffolding network at the nuclear envelope supporting nuclear architecture, A-type lamin-LAP2alpha complexes localize throughout the nucleoplasm. Mutations in A-type lamins cause various human diseases affecting muscle, adipose, skin, and bone tissue, or cause Hutchinson Gilford Progeria. Using a LAP2alpha knockout mouse model, we show that LAP2alpha is required for the localization of a small pool of lamin A/C in the nucleoplasm. The nucleoplasmic lamin A/C-LAP2alpha complex interacts with retinoblastoma protein (pRb) and regulates cell cycle progression in cultured cells. LAP2alpha deficient mice are viable without an overt phenotype. However, in regenerative tissues, such as the epidermis, intestine, skeletal muscle and the hematopoietic system, adult stem cell-derived progenitor cells are hyper-proliferative, yielding higher numbers of progenitor cells in LAP2alpha-deficient tissues. While LAP2alpha-deficient skeletal muscle appeared morphologically normal, immunohistochemical analysis revealed a fiber type switching from slow to fast fibers and a decrease in muscle activity endurance. LAP2alpha-deficient satellite cells proliferated faster than control cells and showed a delayed differentiation to myotubes in vitro. Echocardiography of LAP2alpha-deficient heart revealed impaired heart function, an increased systolic diameter of the left ventricle and fibrosis. Based on these data we propose a model, in which nucleoplasmic LAP2alpha-lamin A/C complexes control adult stem cell activity during tissue homeostasis. Disease-causing mutations in LMNA may alter the interaction with LAP2alpha and affect the nucleoplasmic pool of lamin A and may thus impair adult stem cell proliferation and differentiation and tissue homeostasis in patients.
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