Special Issue "Genetics of Mammalian Meiosis"

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genetics and Genomics".

Deadline for manuscript submissions: closed (15 September 2010)

Special Issue Editors

Guest Editor
Prof. Dr. John Schimenti

Center for Vertebrate Genomics, Cornell University, College of Veterinary Medicine T9014A, Ithaca, NY 14853, USA
Website | E-Mail
Fax: 607-253-3789
Guest Editor
Dr. Paula E. Cohen

Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA
Website | E-Mail
Phone: 607 253 4301
Fax: 607 253 4495

Special Issue Information

Dear Colleagues,

As a process that is central to eukaryotic life, meiosis has been a topic of fascination for generations of biologists. The elegant molecular genetics of fungal systems have led to an impressive understanding of the intricate chromosomal events leading to spore production, and the underlying genetic control of these events. In mammals, the biological complexities associated with spermatogenesis and oogenesis present challenges to defining the genes governing meiosis. However, genomics technologies and animal modeling have enabled remarkable headway in recent years. This special issue will contain reports focusing on the elucidation of genes controlling key aspects of mammalian meiosis (such as recombination, chromosome behavior, and gene regulation), and the unique features of mammalian meiosis that have implications for fertility and fidelity of genome transmission to offspring.

Prof. Dr. John Schimenti
Dr. Paula E. Cohen
Guest Editors

Published Papers (10 papers)

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Research

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Open AccessArticle NEK1 Facilitates Cohesin Removal during Mammalian Spermatogenesis
Genes 2011, 2(1), 260-279; doi:10.3390/genes2010260
Received: 19 January 2011 / Revised: 18 February 2011 / Accepted: 23 February 2011 / Published: 7 March 2011
Cited by 3 | PDF Full-text (1400 KB) | HTML Full-text | XML Full-text
Abstract
Meiosis is a highly conserved process, which is stringently regulated in all organisms, from fungi through to humans. Two major events define meiosis in eukaryotes. The first is the pairing, or synapsis, of homologous chromosomes and the second is the exchange of genetic
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Meiosis is a highly conserved process, which is stringently regulated in all organisms, from fungi through to humans. Two major events define meiosis in eukaryotes. The first is the pairing, or synapsis, of homologous chromosomes and the second is the exchange of genetic information in a process called meiotic recombination. Synapsis is mediated by the meiosis-specific synaptonemal complex structure in combination with the cohesins that tether sister chromatids together along chromosome arms through prophase I. Previously, we identified FKBP6 as a novel component of the mammalian synaptonemal complex. Further studies demonstrated an interaction between FKBP6 and the NIMA-related kinase-1, NEK1. To further investigate the role of NEK1 in mammalian meiosis, we have examined gametogenesis in the spontaneous mutant, Nek1kat2J. Homozygous mutant animals show decreased testis size, defects in testis morphology, and in cohesin removal at late prophase I of meiosis, causing complete male infertility. Cohesin protein SMC3 remains localized to the meiotic chromosome cores at diplonema in the Nek1 mutant, and also in the related Fkbp6 mutant, while in wild type cells SMC3 is removed from the cores at the end of prophase I and becomes more diffuse throughout the DAPI stained region of the nucleus. These data implicate NEK1 as a possible kinase involved in cohesin redistribution in murine spermatocytes. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Open AccessArticle Role of Polycomb Group Protein Cbx2/M33 in Meiosis Onset and Maintenance of Chromosome Stability in the Mammalian Germline
Genes 2011, 2(1), 59-80; doi:10.3390/genes2010059
Received: 30 November 2010 / Revised: 16 December 2010 / Accepted: 6 January 2011 / Published: 11 January 2011
Cited by 9 | PDF Full-text (1102 KB) | HTML Full-text | XML Full-text
Abstract
Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in mice
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Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in mice results in homeotic transformations of the axial skeleton, growth retardation and male-to-female sex reversal. In this study, we tested whether Cbx2 is involved in the control of chromatin remodeling processes during meiosis. Our analysis revealed sex reversal in 28.6% of  XY−/− embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia. Notably, germ cells recovered from Cbx2(XY−/−) testes on day 18.5 of fetal development exhibited premature meiosis onset with synaptonemal complex formation suggesting a role for Cbx2 in the control of meiotic entry in male germ cells. Mutant females exhibited small ovaries with significant germ cell loss and a high proportion of oocytes with abnormal synapsis and non-homologous interactions at the pachytene stage as well as formation of univalents at diplotene. These defects were associated with failure to resolve DNA double strand breaks marked by persistent gH2AX and Rad51 foci at the late pachytene stage. Importantly, two factors required for meiotic silencing of asynapsed chromatin, ubiquitinated histone H2A (ubH2A) and the chromatin remodeling protein BRCA1, co-localized with fully synapsed chromosome axes in the majority of Cbx2(−/−) oocytes. These results provide novel evidence that Cbx2 plays a critical and previously unrecognized role in germ cell viability, meiosis onset and homologous chromosome synapsis in the mammalian germline. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
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Open AccessArticle A Mutation in Mtap2 Is Associated with Arrest of Mammalian Spermatocytes before the First Meiotic Division
Genes 2011, 2(1), 21-35; doi:10.3390/genes2010021
Received: 25 October 2010 / Revised: 7 December 2010 / Accepted: 15 December 2010 / Published: 10 January 2011
Cited by 4 | PDF Full-text (378 KB) | HTML Full-text | XML Full-text
Abstract
In spite of evolutionary conservation of meiosis, many of the genes that control mammalian meiosis are still unknown. We report here that the ENU-induced repro4 mutation, identified in a screen to uncover genes that control mouse meiosis, causes failure of spermatocytes to exit
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In spite of evolutionary conservation of meiosis, many of the genes that control mammalian meiosis are still unknown. We report here that the ENU-induced repro4 mutation, identified in a screen to uncover genes that control mouse meiosis, causes failure of spermatocytes to exit meiotic prophase I via the G2/MI transition. Major events of meiotic prophase I occurred normally in affected spermatocytes and known regulators of the meiotic G2/MI transition were present and functional. Deep sequencing of mutant DNA revealed a mutation located in an intron of the Mtap2 gene, encoding microtubule-associated protein 2, and levels of Mtap2 transcript were reduced in mutant testes. This evidence implicates MTAP2 as required directly or indirectly for completion of meiosis and normal spermatogenesis in mammals. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Figures

Open AccessArticle Synaptonemal Complex Length Variation in Wild-Type Male Mice
Genes 2010, 1(3), 505-520; doi:10.3390/genes1030505
Received: 18 October 2010 / Revised: 18 November 2010 / Accepted: 8 December 2010 / Published: 15 December 2010
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Abstract
Meiosis yields haploid gametes following two successive divisions of a germ cell in the absence of intervening DNA replication. Balanced segregation of homologous chromosomes in Meiosis I is aided by a proteinaceous structure, the synaptonemal complex (SC). The objective of this study was to
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Meiosis yields haploid gametes following two successive divisions of a germ cell in the absence of intervening DNA replication. Balanced segregation of homologous chromosomes in Meiosis I is aided by a proteinaceous structure, the synaptonemal complex (SC). The objective of this study was to determine total average autosomal SC lengths in spermatocytes in three commonly used mouse strains (129S4/SvJae, C57BL/6J, and BALB/c). Our experiments revealed that the total autosomal SC length in BALB/c spermatocytes is 9% shorter than in the two other strains. Shorter SCs are also observed in spermatocytes of (BALB/c × 129S4/SvJae) and (C57BL/6J × BALB/c) F1 hybrids suggesting a genetic basis of SC length regulation. Along these lines, we studied expression of a selected group of genes implicated in meiotic chromosome architecture. We found that BALB/c testes express up to 6-fold less of Rec8 mRNA and 4-fold less of REC8 protein. These results suggest that the mechanism that defines the SC length operates via a REC8‑dependent process. Finally, our results demonstrate that genetic background can have an effect on meiotic studies in mice. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Open AccessArticle A Global Expression Switch Marks Pachytene Initiation during Mouse Male Meiosis
Genes 2010, 1(3), 469-483; doi:10.3390/genes1030469
Received: 18 October 2010 / Revised: 19 November 2010 / Accepted: 1 December 2010 / Published: 13 December 2010
Cited by 15 | PDF Full-text (709 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Male spermatogenesis is an essential and complex process necessary to gain totipotency and allow a whole new organism to develop upon fertilization. While single-gene based studies have provided insights into the mechanisms underlying spermatogenesis, detailed global profiling of all the key meiotic stages
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Male spermatogenesis is an essential and complex process necessary to gain totipotency and allow a whole new organism to develop upon fertilization. While single-gene based studies have provided insights into the mechanisms underlying spermatogenesis, detailed global profiling of all the key meiotic stages is required to fully define these processes. Here, by isolating highly enriched mouse meiotic cell populations, we have generated a comprehensive gene expression atlas of mammalian meiosis. Our data define unique signatures for the specific stages of meiosis, including global chromosome X inactivation and reactivation. The data also reveal profound switches in global gene expression at the initiation of pachynema that are reminiscent of the commitment to meiosis observed in budding yeast. Overall, this meiotic atlas provides an exhaustive blueprint and resource for mammalian gametogenesis and meiosis. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
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Open AccessArticle The Mouse Cohesin-Associated Protein PDS5B Is Expressed in Testicular Cells and Is Associated with the Meiotic Chromosome Axes
Genes 2010, 1(3), 484-494; doi:10.3390/genes1030484
Received: 2 October 2010 / Revised: 18 November 2010 / Accepted: 1 December 2010 / Published: 13 December 2010
Cited by 5 | PDF Full-text (360 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
During the first meiotic prophase, the cohesin complex is localized to the chromosome axis and contributes to chromosome organization, pairing, synapsis, and recombination. The PDS5 protein, an accessory factor of the cohesin complex, is known to be a component of meiotic chromosome cores
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During the first meiotic prophase, the cohesin complex is localized to the chromosome axis and contributes to chromosome organization, pairing, synapsis, and recombination. The PDS5 protein, an accessory factor of the cohesin complex, is known to be a component of meiotic chromosome cores in fungi and to be implicated in meiotic chromosome structure and function. We found by immunoblotting experiments that a mammalian PDS5 protein, PDS5B, is abundantly expressed in mouse testis compared to other tissues. Immunofluorescence labeling experiments revealed that PDS5B is highly expressed in spermatogonia and that most PDS5B is depleted from chromatin as cells enter meiosis. During the first meiotic prophase, PDS5B associates with the axial cores of chromosomes. The axial association of PDS5B was observed also in the absence of synaptonemal complex proteins, such as SYCP1 and SYCP3, suggesting that PDS5B is an integral part of the chromosome axis as defined by the cohesin complex. These results suggest that PDS5B modulates cohesin functions in spermatocytes as well as in spermatogonia, contributing to meiotic chromosome structure and function. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Open AccessArticle Evidence Implicating CCNB1IP1, a RING Domain-Containing Protein Required for Meiotic Crossing Over in Mice, as an E3 SUMO Ligase
Genes 2010, 1(3), 440-451; doi:10.3390/genes1030440
Received: 11 October 2010 / Revised: 10 November 2010 / Accepted: 17 November 2010 / Published: 2 December 2010
Cited by 14 | PDF Full-text (473 KB) | HTML Full-text | XML Full-text
Abstract
The RING domain-containing protein CCNB1IP1 (Cyclin B1 Interacting Protein 1) is a putative ubiquitin E3 ligase that is essential for chiasmata formation, and hence fertility, in mice. Previous studies in cultured cells indicated that CCNB1IP1 targets Cyclin B for degradation, thus playing a
[...] Read more.
The RING domain-containing protein CCNB1IP1 (Cyclin B1 Interacting Protein 1) is a putative ubiquitin E3 ligase that is essential for chiasmata formation, and hence fertility, in mice. Previous studies in cultured cells indicated that CCNB1IP1 targets Cyclin B for degradation, thus playing a role in cell cycle regulation. Mice homozygous for a mutant allele (mei4) of Ccnb1ip1 display no detectable phenotype other than meiotic failure from an absence of chiasmata. CCNB1IP1 is not conserved in key model organisms such as yeast and Drosophila, and there are no features of the protein that implicate clear mechanisms for a role in recombination. To gain insight into CCNB1IP1’s function in meiotic cells, we raised a specific antibody and determined that the protein appears in pachynema. This indicates that CCNB1IP1 is involved with crossover intermediate maturation, rather than early (leptotene) specification of a subset of SPO11-induced double strand breaks towards the crossover pathway. Additionally, a yeast 2-hybrid (Y2H) screen revealed that CCNB1IP1 interacts with SUMO2 and a set of proteins enriched for consensus sumoylation sites. The Y2H studies, combined with scrutiny of CCNB1IP1 domains, implicate this protein as an E3 ligase of the sumoylation cascade. We hypothesize CCNB1IP1 represents a novel meiosis-specific SUMO E3 ligase critical to resolution of recombination intermediates into mature chiasmata. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)

Review

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Open AccessReview Meiosis in a Bottle: New Approaches to Overcome Mammalian Meiocyte Study Limitations
Genes 2011, 2(1), 152-168; doi:10.3390/genes2010152
Received: 7 December 2010 / Revised: 13 January 2011 / Accepted: 19 January 2011 / Published: 14 February 2011
Cited by 3 | PDF Full-text (317 KB) | HTML Full-text | XML Full-text
Abstract
The study of meiosis is limited because of the intrinsic nature of gametogenesis in mammals. One way to overcome these limitations would be the use of culture systems that would allow meiotic progression in vitro. There have been some attempts to culture
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The study of meiosis is limited because of the intrinsic nature of gametogenesis in mammals. One way to overcome these limitations would be the use of culture systems that would allow meiotic progression in vitro. There have been some attempts to culture mammalian meiocytes in recent years. In this review we will summarize all the efforts to-date in order to culture mammalian sperm and oocyte precursor cells. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Open AccessReview Initiation of Meiotic Recombination in Mammals
Genes 2010, 1(3), 521-549; doi:10.3390/genes1030521
Received: 1 November 2010 / Revised: 22 November 2010 / Accepted: 3 December 2010 / Published: 22 December 2010
Cited by 5 | PDF Full-text (1385 KB) | HTML Full-text | XML Full-text
Abstract
Meiotic recombination is initiated by the induction of programmed DNA double strand breaks (DSBs). DSB repair promotes homologous interactions and pairing and leads to the formation of crossovers (COs), which are required for the proper reductional segregation at the first meiotic division. In
[...] Read more.
Meiotic recombination is initiated by the induction of programmed DNA double strand breaks (DSBs). DSB repair promotes homologous interactions and pairing and leads to the formation of crossovers (COs), which are required for the proper reductional segregation at the first meiotic division. In mammals, several hundred DSBs are generated at the beginning of meiotic prophase by the catalytic activity of SPO11. Currently it is not well understood how the frequency and timing of DSB formation and their localization are regulated. Several approaches in humans and mice have provided an extensive description of the localization of initiation events based on CO mapping, leading to the identification and characterization of preferred sites (hotspots) of initiation. This review presents the current knowledge about the proteins known to be involved in this process, the sites where initiation takes place, and the factors that control hotspot localization. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Open AccessReview Cohesin in Oocytes—Tough Enough for Mammalian Meiosis?
Genes 2010, 1(3), 495-504; doi:10.3390/genes1030495
Received: 11 October 2010 / Revised: 22 November 2010 / Accepted: 27 November 2010 / Published: 13 December 2010
PDF Full-text (318 KB) | HTML Full-text | XML Full-text
Abstract
Sister chromatid cohesion is essential for cell division. During meiosis, it is also required for proper synapsis of pairs of sister chromatids and for chiasma formation and maintenance. Since mammalian oocytes remain arrested in late prophase for a very long period—up to five
[...] Read more.
Sister chromatid cohesion is essential for cell division. During meiosis, it is also required for proper synapsis of pairs of sister chromatids and for chiasma formation and maintenance. Since mammalian oocytes remain arrested in late prophase for a very long period—up to five decades in humans—the preservation of cohesion throughout this period is a formidable challenge. Mouse models with cohesin deficiencies and aging wild-type mice showed that this challenge is not fully met: cohesion weakens and deteriorates with increasing age. These recent findings have highly significant implications for our comprehension of the genesis of aneuploidies. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)

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