Loss of nucleoplasmic LAP2α-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation

Lamina-associated polypeptide (LAP) 2 alpha is a chromatin-associated protein that binds A-type lamins(1,2). Mutations in both LAP2 alpha and A-type lamins are linked to human diseases called laminopathies(3), but the molecular mechanisms are poorly understood. The A-type lamin-LAP2a complex interacts with and regulates retinoblastoma protein (pRb)(4,5), but the significance of this interaction in vivo is unknown. Here we address the function of the A-type lamin-LAP2a complex with the use of LAP2 alpha-deficient mice. We show that LAP2a loss causes relocalization of nucleoplasmic A-type lamins to the nuclear envelope and impairs pRb function. This causes inefficient cell-cycle arrest in dense fibroblast cultures and hyperproliferation of epidermal and erythroid progenitor cells in vivo, leading to tissue hyperplasia. Our results support a disease-relevant model(6) in which LAP2a defines A-type lamin localization in the nucleoplasm, which in turn affects pRb-mediated regulation of progenitor cell proliferation and differentiation in highly regenerative tissues.