Expression of Arf tumor suppressor in spermatogonia facilitates meiotic progression in male germ cells Journal Article
| Authors: | Churchman, M. L.; Roig, I.; Jasin, M.; Keeney, S.; Sherr, C. J. |
| Article Title: | Expression of Arf tumor suppressor in spermatogonia facilitates meiotic progression in male germ cells |
| Abstract: | The mammalian Cdkn2a (Ink4a-Arf) locus encodes two tumor suppressor proteins (p16Ink4a and p19Arf) that respectively enforce the anti-proliferative functions of the retinoblastoma protein (Rb) and the p53 transcription factor in response to oncogenic stress. Although p19Arf is not normally detected in tissues of young adult mice, a notable exception occurs in the male germ line, where Arf is expressed in spermatogonia, but not in meiotic spermatocytes arising from them. Unlike other contexts in which the induction of Arf potently inhibits cell proliferation, expression of p19Arf in spermatogonia does not interfere with mitotic cell division. Instead, inactivation of Arf triggers germ cell-autonomous, p53-dependent apoptosis of primary spermatocytes in late meiotic prophase, resulting in reduced sperm production. Arf deficiency also causes premature, elevated, and persistent accumulation of the phosphorylated histone variant H2AX, reduces numbers of chromosome-associated complexes of Rad51 and Dmc1 recombinases during meiotic prophase, and yields incompletely synapsed autosomes during pachynema. Inactivation of Ink4a increases the fraction of spermatogonia in S-phase and restores sperm numbers in Ink4a-Arf doubly deficient mice but does not abrogate γ-H2AX accumulation in spermatocytes or p53-dependent apoptosis resulting from Arf inactivation. Thus, as opposed to its canonical role as a tumor suppressor in inducing p53-dependent senescence or apoptosis, Arf expression in spermatogonia instead initiates a salutary feed-forward program that prevents p53-dependent apoptosis, contributing to the survival of meiotic male germ cells. © 2011 Churchman et al. |
| Keywords: | controlled study; unclassified drug; nonhuman; cell proliferation; mitosis; animal cell; mouse; pachytene; spermatocyte; meiosis; animal tissue; cell survival; cell cycle progression; cell cycle s phase; apoptosis; gene expression profiling; germ cell; gene function; tumor suppressor gene; progeny; gene loss; cell count; gene inactivation; autosome; histone h2ax; bioaccumulation; rad51 protein; prophase; gamma histone h2ax; spermatogenesis; arf gene; recombinase; null cell; dmc1 recombinase; histone phosphorylation; ink4a gene; spermatogonium; spermatozoon maturation |
| Journal Title: | PLoS Genetics |
| Volume: | 7 |
| Issue: | 7 |
| ISSN: | 1553-7390 |
| Publisher: | Public Library of Science |
| Date Published: | 2011-07-01 |
| Start Page: | e1002157 |
| Language: | English |
| DOI: | 10.1371/journal.pgen.1002157 |
| PROVIDER: | scopus |
| PMCID: | PMC3141002 |
| PUBMED: | 21811412 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 October 2011" - "Source: Scopus" |
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138Keeney -
17Roig Navarro -
249Jasin
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