Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination.

TitleAntagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination.
Publication TypeJournal Article
Year of Publication2014
AuthorsQiao, H, Prasada Rao, HBD, Yang, Y, Fong, JH, Cloutier, JM, Deacon, DC, Nagel, KE, Swartz, RK, Strong, E, Holloway, KJ, Cohen, PE, Schimenti, J, Ward, JO, Hunter, N
JournalNat Genet
Date Published2014 Jan 5
ISSN1546-1718
Abstract

<p>Crossover recombination facilitates the accurate segregation of homologous chromosomes during meiosis. In mammals, poorly characterized regulatory processes ensure that every pair of chromosomes obtains at least one crossover, even though most recombination sites yield non-crossovers. Designation of crossovers involves selective localization of the SUMO ligase RNF212 to a minority of recombination sites, where it stabilizes pertinent factors such as MutSγ (ref. 4). Here we show that the ubiquitin ligase HEI10 (also called CCNB1IP1) is essential for this crossover/non-crossover differentiation process. In HEI10-deficient mice, RNF212 localizes to most recombination sites, and dissociation of both RNF212 and MutSγ from chromosomes is blocked. Consequently, recombination is impeded, and crossing over fails. In wild-type mice, HEI10 accumulates at designated crossover sites, suggesting that it also has a late role in implementing crossing over. As with RNF212, dosage sensitivity for HEI10 indicates that it is a limiting factor for crossing over. We suggest that SUMO and ubiquitin have antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and non-crossover sites.</p>

URLhttp://www.ncbi.nlm.nih.gov/pubmed/24390283
DOI10.1038/ng.2858
Alternate JournalNat. Genet.
Refereed DesignationRefereed
Full Text
PubMed ID24390283

A mammal-specific Doublesex homolog associates with male sex chromatin and is required for male meiosis.

TitleA mammal-specific Doublesex homolog associates with male sex chromatin and is required for male meiosis.
Publication TypeJournal Article
Year of Publication2007
AuthorsKim, S, Namekawa, SH, Niswander, LM, Ward, JO, Lee, JT, Bardwell, VJ, Zarkower, D
JournalPLoS Genet
Volume3
Issue4
Paginatione62
Date Published2007 Apr 20
ISSN1553-7404
KeywordsAnimals, Chromatin, DNA-Binding Proteins, Female, Germ Cells, Male, Meiosis, Mice, Mice, Knockout, Protein Binding, Sequence Homology, Sertoli Cells, Sex Chromosomes, Transcription Factors
Abstract

<p>Gametogenesis is a sexually dimorphic process requiring profound differences in germ cell differentiation between the sexes. In mammals, the presence of heteromorphic sex chromosomes in males creates additional sex-specific challenges, including incomplete X and Y pairing during meiotic prophase. This triggers formation of a heterochromatin domain, the XY body. The XY body disassembles after prophase, but specialized sex chromatin persists, with further modification, through meiosis. Here, we investigate the function of DMRT7, a mammal-specific protein related to the invertebrate sexual regulators Doublesex and MAB-3. We find that DMRT7 preferentially localizes to the XY body in the pachytene stage of meiotic prophase and is required for male meiosis. In Dmrt7 mutants, meiotic pairing and recombination appear normal, and a transcriptionally silenced XY body with appropriate chromatin marks is formed, but most germ cells undergo apoptosis during pachynema. A minority of mutant cells can progress to diplonema, but many of these escaping cells have abnormal sex chromatin lacking histone H3K9 di- and trimethylation and heterochromatin protein 1beta accumulation, modifications that normally occur between pachynema and diplonema. Based on the localization of DMRT7 to the XY body and the sex chromatin defects observed in Dmrt7 mutants, we conclude that DMRT7 plays a role in the sex chromatin transformation that occurs between pachynema and diplonema. We suggest that DMRT7 may help control the transition from meiotic sex chromosome inactivation to postmeiotic sex chromatin in males. In addition, because it is found in all branches of mammals, but not in other vertebrates, Dmrt7 may shed light on evolution of meiosis and of sex chromatin.</p>

DOI10.1371/journal.pgen.0030062
Alternate JournalPLoS Genet.
Refereed DesignationRefereed
Full Text
PubMed ID17447844

Toward the genetics of mammalian reproduction: induction and mapping of gametogenesis mutants in mice.

TitleToward the genetics of mammalian reproduction: induction and mapping of gametogenesis mutants in mice.
Publication TypeJournal Article
Year of Publication2003
AuthorsWard, JO, Reinholdt, LG, Hartford, SA, Wilson, LA, Munroe, RJ, Schimenti, KJ, Libby, BJ, O'Brien, M, Pendola, JK, Eppig, J, Schimenti, JC
JournalBiol Reprod
Volume69
Issue5
Pagination1615-25
Date Published2003 Nov
ISSN0006-3363
KeywordsAnimals, Chromosome Mapping, Ethylnitrosourea, Female, Gametogenesis, Genotype, Infertility, Male, Meiosis, Mice, Mutagenesis, Mutagenicity Tests, Mutagens, Mutation, Oocytes, Phenotype, Pregnancy, Reproduction
Abstract

<p>The genetic control of mammalian gametogenesis is inadequately characterized because of a lack of mutations causing infertility. To further the discovery of genes required for mammalian gametogenesis, phenotype-driven screens were performed in mice using random chemical mutagenesis of whole animals and embryonic stem cells. Eleven initial mutations are reported here that affect proliferation of germ cells, meiosis, spermiogenesis, and spermiation. Nine of the mutations have been mapped genetically. These preliminary studies provide baselines for estimating the number of genes required for gametogenesis and offer guidance in conducting new genetic screens that will accelerate and optimize mutant discovery. This report demonstrates the efficacy and expediency of mutagenesis to identify new genes required for mammalian gamete development.</p>

DOI10.1095/biolreprod.103.019877
Alternate JournalBiol. Reprod.
Refereed DesignationRefereed
Full Text
PubMed ID12855593

Mutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over.

TitleMutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over.
Publication TypeJournal Article
Year of Publication2007
AuthorsWard, JO, Reinholdt, LG, Motley, WW, Niswander, LM, Deacon, DC, Griffin, LB, Langlais, KK, Backus, VL, Schimenti, KJ, O'Brien, MJ, Eppig, JJ, Schimenti, JC
JournalPLoS Genet
Volume3
Issue8
Paginatione139
Date Published2007 Aug
ISSN1553-7404
KeywordsAdaptor Proteins, Signal Transducing, Alleles, Animals, Base Pair Mismatch, Cattle, Cell Cycle Proteins, Crossing Over, Genetic, Cyclin-Dependent Kinase 2, Female, Humans, Male, Meiotic Prophase I, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Mutation, Recombination, Genetic, Ubiquitin-Protein Ligases
Abstract

<p>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.</p>

DOI10.1371/journal.pgen.0030139
Alternate JournalPLoS Genet.
Refereed DesignationRefereed
Full Text
PubMed ID17784788

AKAP9 is essential for spermatogenesis and sertoli cell maturation in mice.

TitleAKAP9 is essential for spermatogenesis and sertoli cell maturation in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsSchimenti, KJ, Feuer, SK, Griffin, LB, Graham, NR, Bovet, CA, Hartford, S, Pendola, J, Lessard, C, Schimenti, JC, Ward, JO
JournalGenetics
Volume194
Issue2
Pagination447-57
Date Published2013 Jun
ISSN1943-2631
KeywordsA Kinase Anchor Proteins, Animals, Anti-Mullerian Hormone, Connexin 43, Cyclin-Dependent Kinase Inhibitor p27, Gap Junctions, Male, Meiosis, Mice, Mice, Mutant Strains, Microtubule-Associated Proteins, Organ Specificity, Protein Transport, Sertoli Cells, Spermatogenesis, Spermatozoa, Spindle Apparatus, Thyroid Hormone Receptors alpha, Tight Junctions, Zonula Occludens-1 Protein
Abstract

<p>Mammalian male fertility relies on complex inter- and intracellular signaling during spermatogenesis. Here we describe three alleles of the widely expressed A-kinase anchoring protein 9 (Akap9) gene, all of which cause gametogenic failure and infertility in the absence of marked somatic phenotypes. Akap9 disruption does not affect spindle nucleation or progression of prophase I of meiosis but does inhibit maturation of Sertoli cells, which continue to express the immaturity markers anti-Mullerian hormone and thyroid hormone receptor alpha in adults and fail to express the maturation marker p27(Kip1). Furthermore, gap and tight junctions essential for blood-testis barrier (BTB) organization are disrupted. Connexin43 (Cx43) and zona occludens-1 are improperly localized in Akap9 mutant testes, and Cx43 fails to compartmentalize germ cells near the BTB. These results identify and support a novel reproductive tissue-specific role for Akap9 in the coordinated regulation of Sertoli cells in the testis.</p>

DOI10.1534/genetics.113.150789
Alternate JournalGenetics
Refereed DesignationRefereed
Full Text
PubMed ID23608191

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