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  • Original Paper
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Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number

Abstract

Lack of Cdk4 expression in mice leads to insulin-deficient diabetes and female infertility owing to a reduced number of pancreatic β cells and prolactin-producing pituitary lactotrophs, respectively. Cdk4 null mice display also reduced body and organ size. Here, we show that Cdk4 is essential for the postnatal proliferation of pancreatic β cells but not for embryonic neogenesis from ductal epithelial cells. Re-expression of endogenous Cdk4 in β cells and in the pituitary gland of Cdk4 null mice restores cell proliferation and results in fertile and normoglycemic animals, thus, demonstrating that the proliferation defects in these cellular populations are cell autonomous because of the lack of Cdk4 expression. However, these mice remain small in size, indicating that this phenotype is not because of pancreatic- or pituitary-mediated endocrine defects. This phenotype is a consequence of reduced cell numbers rather than reduced cell size. Thus, mammalian Cdk4 is not only involved in controlling proliferation of specific cell types but may play a wider role in establishing homeostatic cell numbers.

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Acknowledgements

We thank Ernesto de la Cueva, Maribel Muñoz, Marta San Román, Ignacio Segovia, Michelle Turmo and Raquel Villar for their excellent technical assistance. This work was supported by Grants from the Spanish Ministerio of Educación y Cultura (to SO and MB), Ligue contre le Cancer (Comité de Dordogne) and INSERM (to PD) and Fundación Pfizer (to MB). JM and RS were supported in part by fellowships from the Fondo de Investigación Sanitaria, SLH by a postdoctoral fellowship from the Comunidad Autónoma de Madrid and FN-P by a fellowship from the Foundation pour la Recherche Médicale.

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Correspondence to Sagrario Ortega.

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Martín, J., Hunt, S., Dubus, P. et al. Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number. Oncogene 22, 5261–5269 (2003). https://doi.org/10.1038/sj.onc.1206506

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