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Molecular and Cellular Biology, August 2003, p. 5256-5268, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5256-5268.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Rb and N-ras Function Together To Control Differentiation in the Mouse

Chiaki Takahashi,^1, Roderick T. Bronson,^2,3 Merav Socolovsky,⁴ Bernardo Contreras,¹ Kwang Youl Lee,^1, Tyler Jacks,⁵ Makoto Noda,⁶ Raju Kucherlapati,⁷ and Mark E. Ewen^1*

Department of Medical Oncology and Medicine, Dana-Farber Cancer Institute and Harvard Medical School,¹ Rodent Histopathology Core,³ Harvard-Partners Center for Genetics and Genomics, Harvard Medical School, Boston, Massachusetts 02115,⁷ Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111,² Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142,⁴ Department of Biology and Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,⁵ Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan⁶

Received 8 November 2002/ Returned for modification 7 January 2003/ Accepted 30 April 2003

The product of the retinoblastoma tumor suppressor gene (Rb) can control cell proliferation and promote dif-ferentiation. Murine embryos nullizygous for Rb die midgestation with defects in cell cycle regulation, control of apoptosis, and terminal differentiation of several tissues, including skeletal muscle, nervous system, and lens. Previous cell culture-based experiments have suggested that the retinoblastoma protein (pRb) and Ras operate in a common pathway to control cellular differentiation. Here we have tested the hypothesis that the proto-oncogene N-ras participates in Rb-dependent regulation of differentiation by generating and characterizing murine embryos deficient in both N-ras and Rb. We show that deletion of N-ras rescues a unique subset of the developmental defects associated with nullizygosity of Rb, resulting in a significant extension of life span. Rb^-/-; N-ras^-/- skeletal muscle has normal fiber density, myotube length and thickness, in contrast to Rb-deficient embryos. Additionally, Rb^-/-; N-ras^-/- muscle shows a restoration in the expression of the late muscle-specific gene MCK, and this correlates with a significant potentiation of MyoD transcriptional activity in Rb^-/-; N-ras^-/-, compared to Rb^-/- myoblasts in culture. The improved differentiation of skeletal muscle in Rb^-/-; N-ras^-/- embryos occurs despite evidence of deregulated proliferation and apoptosis, as seen in Rb-deficient animals. Our findings suggest that the control of differentiation and proliferation by Rb are genetically separable.

Present addresses: Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan.

Present address: Chung-buk National University, College of Medicine, Cheong-Ju, Korea.

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