title: Disruption of CHTF18 causes defective meiotic recombination in male mice.
abstract: CHTF18 (chromosome transmission fidelity factor 18) is an evolutionarily conserved subunit of the Replication Factor C-like complex, CTF18-RLC. CHTF18 is necessary for the faithful passage of chromosomes from one daughter cell to the next during mitosis in yeast, and it is crucial for germline development in the fruitfly. Previously, we showed that mouse Chtf18 is expressed throughout the germline, suggesting a role for CHTF18 in mammalian gametogenesis. To determine the role of CHTF18 in mammalian germ cell development, we derived mice carrying null and conditional mutations in the Chtf18 gene. Chtf18-null males exhibit 5-fold decreased sperm concentrations compared to wild-type controls, resulting in subfertility. Loss of Chtf18 results in impaired spermatogenesis; spermatogenic cells display abnormal morphology, and the stereotypical arrangement of cells within seminiferous tubules is perturbed. Meiotic recombination is defective and homologous chromosomes separate prematurely during prophase I. Repair of DNA double-strand breaks is delayed and incomplete; both RAD51 and γH2AX persist in prophase I. In addition, MLH1 foci are decreased in pachynema. These findings demonstrate essential roles for CHTF18 in mammalian spermatogenesis and meiosis, and suggest that CHTF18 may function during the double-strand break repair pathway to promote the formation of crossovers.
authors.affiliation: Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, PA, USA. kberkowitz@drexelmed.edu
authors.forename: Karen M
authors.initials: KM
authors.lastname: Berkowitz
authors.forename: Aislinn R
authors.initials: AR
authors.lastname: Sowash
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Koenig
authors.forename: Dawnette
authors.initials: D
authors.lastname: Urcuyo
authors.forename: Fahmida
authors.initials: F
authors.lastname: Khan
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: Wang
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jongens
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D005854:Germ Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007246:Infertility / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics*; D049469:Meiotic Prophase I; D051379:Mice; D009687:Nuclear Proteins; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics*; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000473:pathology
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins; D006657:Histones; D009687:Nuclear Proteins; D051135:Rad51 Recombinase; C580921:CHTF18 protein, mouse; C475961:gamma-H2AX protein, mouse