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  • The EMBO Journal (2001) 20, 3402 - 3413
  • doi:10.1093/emboj/20.13.3402

Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system

Marta M. Lipinski1, Kay F. Macleod2, Bart O. Williams3, Tara L. Mullaney1, Denise Crowley1,4 and Tyler Jacks1,4

  1. Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, UK
  2. Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
  3. Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 495030, UK
  4. Howard Hughes Medical Institute, 400 Jones Bridge Road, Chevy Chase, MD 20815, USA

Correspondence to:

Tyler Jacks, E-mail: tjacks@mit.edu

Received 20 November 2000; Accepted 14 May 2001; Revised 11 May 2001

The retinoblastoma tumor suppressor (RB) plays an important role in the regulation of cell cycle progression and terminal differentiation of many cell types. Rb-/- mouse embryos die at midgestation with defects in cell cycle regulation, control of apoptosis and terminal differentiation. However, chimeric mice composed of wild-type and Rb-deficient cells are viable and show minor abnormalities. To determine the role of Rb in development more precisely, we analyzed chimeric embryos and adults made with marked Rb-/- cells. Like their germline Rb-/- counterparts, brains of midgestation chimeric embryos exhibited extensive ectopic S-phase entry. In Rb-mutants, this is accompanied by widespread apoptosis. However, in chimeras, the majority of Rb-deficient cells survived and differentiated into neuronal fates. Rescue of Rb-/- neurons in the presence of wild-type cells occurred after induction of the p53 pathway and led to accumulation of cells with 4n DNA content. Therefore, the role of Rb during development can be divided into a cell-autonomous function in exit from the cell cycle and a non-cell-autonomous role in the suppression of apoptosis and induction of differentiation.

  • Keywords:

    • apoptosis,
    • cell cycle,
    • central nervous system,
    • differentiation,
    • retinoblastoma