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Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

¹ Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain
² Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Center, 28029 Madrid, Spain
³ National Cancer Institute, Frederick, MD 21702
⁴ Division of Matrix Biology, Department of Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Correspondence to Carlos López-Otín: clo{at}uniovi.es

Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments. To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24-null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region. These alterations are rescued in Zmpste24^–/–Lmna^+/– mutant mice, which do not manifest progeroid symptoms. We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24^–/– mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction.

J. Cadiñanos's present address is Sanger Institute, Cambridge CB10 1SA, UK.

A.M. Pendás's present address is Instituto de Biologia Molecular y Celular del Cancer, Consejo Superior de Investigaciones Cientificas, Universidad de Salamanca, 37007 Salamanca, Spain.

Abbreviations used in this paper: 5mC, 5-methylcytosine; LRC, label-retaining cell; Mitf, microphthalmia transcription factor; TPA, tetradecanoylphorbol 13-acetate.

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