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 (p16(Ink4a) and p19(Arf)) that respectively enforce the anti-proliferative functions of the retinoblastoma protein (Rb) and the p53 transcription factor in response to oncogenic stress. Although p19(Arf) 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 p19(Arf) 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.
authors.affiliation: Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Churchman
authors.forename: Ignasi
authors.initials: I
authors.lastname: Roig
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Scott
authors.initials: S
authors.lastname: Keeney
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Sherr
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005640:Follicle Stimulating Hormone / Q000097:blood; D006657:Histones / Q000378:metabolism; D015151:Immunoblotting; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D051135:Rad51 Recombinase / Q000378:metabolism; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism*; D013094:Spermatozoa / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C513032:Dmc1 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D051135:Rad51 Recombinase