Loss of nucleoplasmic LAP2alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation.
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.
Max F. Perutz Laboratories, Medical University of Vienna and University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
Nana
N
Naetar
Barbara
B
Korbei
Serguei
S
Kozlov
Marc A
MA
Kerenyi
Daniela
D
Dorner
Rosana
R
Kral
Ivana
I
Gotic
Peter
P
Fuchs
Tatiana V
TV
Cohen
Reginald
R
Bittner
Colin L
CL
Stewart
Roland
R
Foisner
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D015672:Erythroid Precursor Cells / Q000502:physiology*; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2