Journal
CELL STEM CELL
Volume 7, Issue 2, Pages 198-213Publisher
CELL PRESS
DOI: 10.1016/j.stem.2010.05.022
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Funding
- The Developmental and Neonatal Biology Program [2T32 HD007249]
- NIH [5T32 AI07328, 5T32 HD007249, F32 AR051678-01, AG009521, AG020961, HL096113]
- MDA [4320]
- LLS [TR6025-09]
- JDRF [34-2008-623]
- CIRM [RT1-01001]
- Baxter Foundation
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An outstanding biological question is why tissue regeneration in mammals is limited, whereas urodele amphibians and teleost fish regenerate major structures, largely by cell cycle reentry. Upon inactivation of Rb, proliferation of postmitotic urodele skeletal muscle is induced, whereas in mammalian muscle this mechanism does not exist. We postulated that a tumor suppressor present in mammals but absent in regenerative vertebrates, the Ink4a product ARF (alternative reading frame), is a regeneration suppressor. Concomitant inactivation of Ad and Rb led to mammalian muscle cell cycle reentry, loss of differentiation properties, and upregulation of cytokinetic machinery. Single postmitotic myocytes were isolated by laser micro-dissection-catapulting, and transient suppression of Art and Rb yielded myoblast colonies that retained the ability to differentiate and fuse into myofibers upon transplantation in vivo. These results show that differentiation of mammalian cells is reversed by inactivation of Ad and Rb and support the hypothesis that Ad evolved at the expense of regeneration.
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