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Molecular and Cellular Biology, April 2009, p. 1895-1908, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01885-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Distinct Developmental Roles of Cell Cycle Inhibitors p57^Kip2 and p27^Kip1 Distinguish Pituitary Progenitor Cell Cycle Exit from Cell Cycle Reentry of Differentiated Cells ^,

Steve Bilodeau, Audrey Roussel-Gervais, and Jacques Drouin^*

Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, Quebec H2W 1R7, Canada

Received 11 December 2008/ Accepted 4 January 2009

Patterning and differentiation signals are often believed to drive the developmental program, including cell cycle exit of proliferating progenitors. Taking advantage of the spatial and temporal separation of proliferating and differentiated cells within the developing anterior pituitary gland, we investigated the control of cell proliferation during organogenesis. Thus, we identified a population of noncycling precursors that are uniquely marked by expression of the cell cycle inhibitor p57^Kip2 and by cyclin E. In p57^Kip2–/– mice, the developing pituitary is hyperplastic due to accumulation of proliferating progenitors, whereas overexpression of p57^Kip2 leads to hypoplasia. p57^Kip2-dependent cell cycle exit is not required for differentiation, and conversely, blockade of cell differentiation, as achieved in Tpit^–/– pituitaries, does not prevent cell cycle exit but rather leads to accumulation of p57^Kip2-positive precursors. Upon differentiation, p57^Kip2 is replaced by p27^Kip1. Accordingly, proliferating differentiated cells are readily detected in p27^Kip1–/– pituitaries but not in wild-type or p57^Kip2–/– pituitaries. Strikingly, all cells of p57^Kip2–/–;p27^Kip1–/– pituitaries are proliferative. Thus, during normal development, progenitor cell cycle exit is controlled by p57^Kip2 followed by p27^Kip1 in differentiated cells; these sequential actions, taken together with different pituitary outcomes of their loss of function, suggest hierarchical controls of the cell cycle that are independent of differentiation.

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* Corresponding author. Mailing address: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, Quebec, Canada H2W 1R7. Phone: (514) 987-5680. Fax: (514) 987-5575. E-mail: jacques.drouin{at}ircm.qc.ca

Published ahead of print on 12 January 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, April 2009, p. 1895-1908, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01885-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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