CTF18 plays an important role in mammalian gametogenesis and fertility

Abstract

OBJECTIVE: CTF18 encodes an evolutionarily conserved protein that is crucial for germline development in the fly and that is essential for faithful transmission of chromosomes during DNA replication in yeast. Recently we demonstrated that CTF18, termed Chtf18 in mice, is expressed throughout the male and female germline of the mouse. The objective of our studies is to elucidate the role of CTF18/Chtf18 in mammalian germ cell development.DESIGN: We generated a mouse model that lacks Chtf18 to directly determine the role of Chtf18 in vivo.MATERIALS AND METHODS: We employed gene targeting to derive mice that lack Chtf18 function. We utilized Cre/loxP technology to derive Chtf18-null and conditional alleles. The phenotypic consequences of Chtf18 deletion were assessed by gross, histological, chromosomal, and immunofluorescence examination of Chtf18-deficient and wild-type gonads.RESULTS: Adult Chtf18-null male and female mouse gonads are much smaller and morphologically abnormal compared to those of their wild-type adult littermates. Fertility is significantly impaired in both male and female mice. Seminiferous tubules from Chtf18-null males demonstrate an overall deficiency of spermatocytes and a significant paucity of spermatids and spermatozoa. Some areas of seminiferous tubules are almost devoid of spermatogenic cells. The tubules also contain large multi-nucleated and aberrant-appearing spermatogenic cells. Ovaries from Chtf18-null females are smaller and contain fewer follicles than wild-type females. All stages of follicle development are seen, but many of the follicles appear to be degenerating and contain aberrant-appearing cells. Surface spread nuclei from Chtf18-null mouse gonads reveal a clear chromosomal defect during meiosis. In addition, the morphological phenotype of Chtf18loxP/loxP; TNAP Cre mice, in which Chtf18 is deleted only in germ cells, is indistinguishable from that of Chtf18-null gonads, indicating that Chtf18 is required in the germ line.CONCLUSIONS: CTF18/Chtf18 plays a significant role in mammalian gametogenesis and fertility through a function in meiosis. OBJECTIVE: CTF18 encodes an evolutionarily conserved protein that is crucial for germline development in the fly and that is essential for faithful transmission of chromosomes during DNA replication in yeast. Recently we demonstrated that CTF18, termed Chtf18 in mice, is expressed throughout the male and female germline of the mouse. The objective of our studies is to elucidate the role of CTF18/Chtf18 in mammalian germ cell development. DESIGN: We generated a mouse model that lacks Chtf18 to directly determine the role of Chtf18 in vivo. MATERIALS AND METHODS: We employed gene targeting to derive mice that lack Chtf18 function. We utilized Cre/loxP technology to derive Chtf18-null and conditional alleles. The phenotypic consequences of Chtf18 deletion were assessed by gross, histological, chromosomal, and immunofluorescence examination of Chtf18-deficient and wild-type gonads. RESULTS: Adult Chtf18-null male and female mouse gonads are much smaller and morphologically abnormal compared to those of their wild-type adult littermates. Fertility is significantly impaired in both male and female mice. Seminiferous tubules from Chtf18-null males demonstrate an overall deficiency of spermatocytes and a significant paucity of spermatids and spermatozoa. Some areas of seminiferous tubules are almost devoid of spermatogenic cells. The tubules also contain large multi-nucleated and aberrant-appearing spermatogenic cells. Ovaries from Chtf18-null females are smaller and contain fewer follicles than wild-type females. All stages of follicle development are seen, but many of the follicles appear to be degenerating and contain aberrant-appearing cells. Surface spread nuclei from Chtf18-null mouse gonads reveal a clear chromosomal defect during meiosis. In addition, the morphological phenotype of Chtf18loxP/loxP; TNAP Cre mice, in which Chtf18 is deleted only in germ cells, is indistinguishable from that of Chtf18-null gonads, indicating that Chtf18 is required in the germ line. CONCLUSIONS: CTF18/Chtf18 plays a significant role in mammalian gametogenesis and fertility through a function in meiosis.