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Vol. 16, Issue 3, 1469-1480, March 2005

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p27^Kip1 Acts Downstream of N-Cadherin-mediated Cell Adhesion to Promote Myogenesis beyond Cell Cycle Regulation

Istituto Pasteur-Fondazione Cenci-Bolognetti, Dipartimento di Biologia Cellulare e dello Sviluppo, Università di Roma "La Sapienza", 00185 Roma, Italy

Submitted July 21, 2004; Revised December 2, 2004; Accepted December 23, 2004
Monitoring Editor: Richard Assoian

It is widely acknowledged that cultured myoblasts can not differentiate at very low density. Here we analyzed the mechanism through which cell density influences myogenic differentiation in vitro. By comparing the behavior of C2C12 myoblasts at opposite cell densities, we found that, when cells are sparse, failure to undergo terminal differentiation is independent from cell cycle control and reflects the lack of p27^Kip1 and MyoD in proliferating myoblasts. We show that inhibition of p27^Kip1 expression impairs C2C12 cell differentiation at high density, while exogenous p27^Kip1 allows low-density cultured C2C12 cells to enter the differentiative program by regulating MyoD levels in undifferentiated myoblasts. We also demonstrate that the early induction of p27^Kip1 is a critical step of the N-cadherin-dependent signaling involved in myogenesis. Overall, our data support an active role of p27^Kip1 in the decision of myoblasts to commit to terminal differentiation, distinct from the regulation of cell proliferation, and identify a pathway that, reasonably, operates in vivo during myogenesis and might be part of the phenomenon known as "community effect".

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

^* Present address: Department of Immunology and Pathology, Institute of Animal Health, Pirbright Surrey, GU24 ONF United Kingdom.

Address correspondence to: Milena Grossi (milena.grossi{at}uniroma1.it).

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