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Cell‐autonomous and non‐cell‐autonomous functions of the Rb tumor suppressor in developing central nervous system
Author(s) -
Lipinski Marta M.,
Macleod Kay F.,
Williams Bart O.,
Mullaney Tara L.,
Crowley Denise,
Jacks Tyler
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.13.3402
Subject(s) - biology , central nervous system , suppressor , cell , nervous system , microbiology and biotechnology , neuroscience , genetics , cancer
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.