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

Nature Cell Biology volume 10, pages 1341–1348 (2008)Cite this article

Abstract

Lamina-associated polypeptide (LAP) 2α is a chromatin-associated protein that binds A-type lamins1,2. Mutations in both LAP2α and A-type lamins are linked to human diseases called laminopathies3, but the molecular mechanisms are poorly understood. The A-type lamin–LAP2α 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–LAP2α complex with the use of LAP2α-deficient mice. We show that LAP2α 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 model6 in which LAP2α 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.

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Figure 1: Lap2α−/− fibroblasts have reduced nucleoplasmic lamin A/C levels.
Figure 2: Loss of LAP2α in fibroblasts impairs cell-cycle arrest.
Figure 3: LAP2α-deficient paw epidermis contains a higher number of proliferating progenitor cells causing epidermal hyperplasia.
Figure 4: Loss of nucleoplasmic lamins A and C is linked to epidermal hyperproliferation.
Figure 5: Absence of LAP2α leads to elevated levels of erythroid progenitors.

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Acknowledgements

We thank W. Müller for the Cre-deleter mouse strain, Larry Gerace for the genomic BAC clone, T. Jacks for triple knockout mouse embryonic fibroblasts, P. Luvalle for providing paws from lamin A/C-deficient mice, K. Biadasiewicz for expert technical assistance, and H. Beug and E. W. Müllner for helpful discussions. This study was supported by grants from the Austrian Science Research Fund (FWF P17871) and the EURO-Laminopathies research project of the European Commission (contract LSHM-CT-2005-018690) to R.F. and a postdoctoral fellowship from L'Oreal/UNESCO/ÖADW/BMWF to N.N.

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Author notes

  1. Colin L. Stewart

    Present address: Present address: Institute of Medical Biology, 8A Biomedical Grove no. 06-40, Immunos, Singapore 138648.,

  2. Nana Naetar and Barbara Korbei: These authors contributed equally to this work.

Authors and Affiliations

  1. Max F. Perutz Laboratories, Medical University of Vienna and University of Vienna, Dr. Bohr-Gasse 9, A-1030, Vienna, Austria

    Nana Naetar, Barbara Korbei, Marc A. Kerenyi, Daniela Dorner, Rosana Kral, Ivana Gotic, Peter Fuchs & Roland Foisner

  2. Advanced BioScience Laboratories, Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, 21702, Maryland, USA

    Serguei Kozlov, Tatiana V. Cohen & Colin L. Stewart

  3. Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, A-1030, Vienna, Austria

    Marc A. Kerenyi

  4. Neuromuscular Research Center, Center for Anatomy and Cell Biology, Medical University of Vienna, Schwarzspanierstr. 17, A-1090, Vienna, Austria

    Reginald Bittner

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Contributions

N.N., B.K., P.F., C.L.S. and R.F. planned the project; N.N., B.K., S.K., M.A.K., D.D., R.K., I.G. and T.C. performed the experiments; N.N., B.K., M.A.K., D.D., R.B. and R.F. analysed the data; N.N., B.K., C.L.S. and R.F. wrote the manuscript.

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Correspondence to Roland Foisner.

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Naetar, N., Korbei, B., Kozlov, S. et al. Loss of nucleoplasmic LAP2α–lamin A complexes causes erythroid and epidermal progenitor hyperproliferation. Nat Cell Biol 10, 1341–1348 (2008). https://doi.org/10.1038/ncb1793

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