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.
Highlights
Precise chromosome segregation is crucial to ensure that germ cell development proceeds normally during meiosis, and that genetic information is accurately transmitted to the gametes
Meiosis is the specialized process of cell division during germ cell development that results in formation of eggs and sperm
Genetic exchange between maternal and paternal chromosomes occurs during meiosis in a process called homologous recombination, in which DNA doublestrand breaks are made and repaired to allow DNA crossovers to form
Summary
Precise chromosome segregation is crucial to ensure that germ cell development proceeds normally during meiosis, and that genetic information is accurately transmitted to the gametes. For chromosome segregation to proceed flawlessly during meiosis, homologous chromosomes must undergo several processes that allow them to pair and remain physically joined until anaphase I. Sister chromatids are connected between arms and at centromeres by cohesion, a process mediated by cohesins, i.e. multiprotein complexes that are established during S-phase [1,2,3,4,5,6]. The physical connection between homologues occurs by synapsis during meiotic prophase I, when homologous chromosomes pair through formation of a tripartite protein structure: the synaptonemal complex (for a review see [9]). At the end of prophase I, the synaptonemal complex disassembles, but homologous chromosomes remain joined across sister chromatid arms and at centromeres. Cohesion and chiasmata between sister chromatid arms prevent homologues from separating prematurely [10,11]
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