期刊
PLOS GENETICS
卷 3, 期 8, 页码 1550-1563出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.0030139
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资金
- NCI NIH HHS [P30 CA034196, CA34196] Funding Source: Medline
- NCRR NIH HHS [P20 RR16462, P20 RR016462] Funding Source: Medline
- NIGMS NIH HHS [GM45415, GM66650-01, R15 GM078183, GM64275-01A, F32 GM066650, R15 GM078183-01, R01 GM045415, F32 GM064275] Funding Source: Medline
Crossing over during meiotic prophase I is required for sexual reproduction in mice and contributes to genome-wide genetic diversity. Here we report on the characterization of an N-ethyl-N-nitrosourea-induced, recessive allele called mei4, which causes sterility in both sexes owing to meiotic defects. In mutant spermatocytes, chromosomes fail to congress properly at the metaphase plate, leading to arrest and apoptosis before the first meiotic division. Mutant oocytes have a similar chromosomal phenotype but in vitro can undergo meiotic divisions and fertilization before arresting. During late meiotic prophase in mei4 mutant males, absence of cyclin dependent kinase 2 and mismatch repair protein association from chromosome cores is correlated with the premature separation of bivalents at diplonema owing to lack of chiasmata. We have identified the causative mutation, a transversion in the 59 splice donor site of exon 1 in the mouse ortholog of Human Enhancer of Invasion 10 ( Hei10; also known as Gm288 in mouse and CCNB1IP1 in human), a putative B-type cyclin E3 ubiquitin ligase. Importantly, orthologs of Hei10 are found exclusively in deuterostomes and not in more ancestral protostomes such as yeast, worms, or flies. The cloning and characterization of the mei4 allele of Hei10 demonstrates a novel link between cell cycle regulation and mismatch repair during prophase I.
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