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

Abstract

Lamina-associated polypeptide (LAP) 2alpha is a chromatin-associated protein that binds A-type lamins. Mutations in both LAP2alpha and A-type lamins are linked to human diseases called laminopathies, but the molecular mechanisms are poorly understood. The A-type lamin-LAP2alpha complex interacts with and regulates retinoblastoma protein (pRb), but the significance of this interaction in vivo is unknown. Here we address the function of the A-type lamin-LAP2alpha complex with the use of LAP2alpha-deficient mice. We show that LAP2alpha 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 in which LAP2alpha 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.

A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha

“…Mature lamin A/C in the nuclear interior colocalizes with LAP2alpha (Dechat et al 2000;Naetar et al 2008). As euchromatic regions associated with lamin A/C were largely congruent with those bound by LAP2alpha, it is conceivable that euchromatin-associated lamin A/C is predominantly localized in the nuclear interior, whereas heterochromatin-bound lamin A/C is part of the peripheral lamina.…”

“…Thus, A-type lamins can dissociate from the membrane into the nucleoplasm, where they interact with the non-membrane-bound LAP2 isoform, LAP2alpha (Dechat et al 2000). Deletion of exon 4 of the Tmpo gene generated mice specifically lacking LAP2alpha and leads to the selective loss of nucleoplasmic lamin A/C (Naetar et al 2008). Loss of LAP2alpha causes tissue-specific phenotypes, including increased proliferation of tissue progenitor cells in epidermis, colon, and the hematopoietic system (Naetar et al 2008), delayed skeletal muscle differentiation (Gotic et al 2010b), and impaired heart function (Gotic et al 2010a).…”

Lamins at a glance

“…Loss of lamins A and C results in reduced levels of pRb as a result of proteolytic degradation, leading to altered cell cycle dynamics (Johnson et al, 2004;Markiewicz et al, 2002a;Moiseeva et al, 2011;Nitta et al, 2007). Furthermore, complex formation between lamin A, LAP2a and pRb controls nucleoplasmic anchoring of pRb and modulates E2F-dependent transcription (Dorner et al, 2006;Markiewicz et al, 2002a;Naetar et al, 2008;Pekovic et al, 2007). Finally, lamin A also serves as a mutually exclusive binding partner for extracellular-signal-regulated kinases 1 and 2 (ERK1/2; MAPK3 and MAPK1, repectively) and pRb; activated ERK1/2 disrupt nuclear complexes of lamin A and pRb, and thereby promote E2F activation (Rodríguez et al, 2010).…”

Nuclear lamins: key regulators of nuclear structure and activities

“…At [112,113] [92,115,116]. Because lack of A-type lamins or the expression of disease-causing mutant lamin A affect the cell cycle, as well as differentiation of myocytes and adipocytes [117][118][119], it has been proposed that lamins A and C-LAP-2␣ complexes also control the balance between proliferation and differentiation of adult stem cells in tissue homeostasis and regeneration (see below) [120,121]. Interestingly, while mouse fibroblasts derived from Lmnanull or LAP-2␣-null cells showed accelerated proliferation, human dermal fibroblasts down-regulation of either lamins A and C or LAP-2␣ showed G1 cell cycle arrest [122].…”