Mutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over.
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 5' 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.
Ward
Jeremy O
JO
Middlebury College, Middlebury, Vermont, United States of America. jward@middlebury.edu
Reinholdt
Laura G
LG
Motley
William W
WW
Niswander
Lisa M
LM
Deacon
Dekker C
DC
Griffin
Laurie B
LB
Langlais
Kristofor K
KK
Backus
Vickie L
VL
Schimenti
Kerry J
KJ
O'Brien
Marilyn J
MJ
Eppig
John J
JJ
Schimenti
John C
JC
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics; D002417:Cattle; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D003434:Crossing Over, Genetic / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D049469:Meiotic Prophase I / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011995:Recombination, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology