Article

Hormad1 Mutation Disrupts Synaptonemal Complex Formation, Recombination, and Chromosome Segregation in Mammalian Meiosis

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Genetics (Impact Factor: 7.53). 11/2010; 6(11):e1001190. DOI: 10.1371/journal.pgen.1001190
Source: PubMed

ABSTRACT

Meiosis is unique to germ cells and essential for reproduction. During the first meiotic division, homologous chromosomes pair, recombine, and form chiasmata. The homologues connect via axial elements and numerous transverse filaments to form the synaptonemal complex. The synaptonemal complex is a critical component for chromosome pairing, segregation, and recombination. We previously identified a novel germ cell-specific HORMA domain encoding gene, Hormad1, a member of the synaptonemal complex and a mammalian counterpart to the yeast meiotic HORMA domain protein Hop1. Hormad1 is essential for mammalian gametogenesis as knockout male and female mice are infertile. Hormad1 deficient (Hormad1(-/) (-)) testes exhibit meiotic arrest in the early pachytene stage, and synaptonemal complexes cannot be visualized by electron microscopy. Hormad1 deficiency does not affect localization of other synaptonemal complex proteins, SYCP2 and SYCP3, but disrupts homologous chromosome pairing. Double stranded break formation and early recombination events are disrupted in Hormad1(-/) (-) testes and ovaries as shown by the drastic decrease in the γH2AX, DMC1, RAD51, and RPA foci. HORMAD1 co-localizes with γH2AX to the sex body during pachytene. BRCA1, ATR, and γH2AX co-localize to the sex body and participate in meiotic sex chromosome inactivation and transcriptional silencing. Hormad1 deficiency abolishes γH2AX, ATR, and BRCA1 localization to the sex chromosomes and causes transcriptional de-repression on the X chromosome. Unlike testes, Hormad1(-/) (-) ovaries have seemingly normal ovarian folliculogenesis after puberty. However, embryos generated from Hormad1(-/) (-) oocytes are hyper- and hypodiploid at the 2 cell and 8 cell stage, and they arrest at the blastocyst stage. HORMAD1 is therefore a critical component of the synaptonemal complex that affects synapsis, recombination, and meiotic sex chromosome inactivation and transcriptional silencing.

    • "Several genetic, epigenetic and biochemical mechanisms have been proposed from different research groups, including defective spindle assembly checkpoint (Jones and Lane 2013; Yun et al. 2014), weakened centromere cohesion (Chiang et al. 2010; Eichenlaub-Ritter 2012; Tsutsumi et al. 2014), alterations in the pattern of histone covalent modifications (Akiyama et al. 2006; Yang et al. 2012; Luo et al. 2013; Ma and Schultz 2013), altered microtubule–kinetochore interactions (Shomper et al. 2014), sites and level of recombination (Cheng et al. 2009; Shin et al. 2010; Li et al. 2011), cell cycle regulation defects (Homer et al. 2005; Nabti et al. 2014) and mitochondrial dysfunction (Bartmann et al. 2004; Eichenlaub- Ritter et al. 2004). While this intricate scenario likely indicates that the origin of aneuploidy is multifactorial and aneuploidies arise from different mechanisms, some conditions in the mother, such as age (te Velde and Pearson 2002) or obesity (Luzzo et al. 2012), are known to increase the occurrence of chromosomal mis-segregation. "
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    ABSTRACT: Implantation failure and genetic developmental disabilities in mammals are caused by errors in chromosome segregation originating mainly in the oocyte during meiosis I. Some conditions, like maternal ageing or in vitro maturation (IVM), increase the incidence of oocyte aneuploidy. Here oocytes from adult mares were used to investigate oocyte maturation in a monovulatory species. Experiments were conducted to compare: (1) the incidence of aneuploidy, (2) the morphology of the spindle, (3) the acetylation of lysine 16 on histone H4 (H4K16) and (4) the relative amount of histone acetyltransferase 1 (HAT1), K(lysine) acetyltransferase 8 (KAT8, also known as MYST1), histone deacetylase 1 (HDAC1) and NAD-dependent protein deacetylase sirtuin 1 (SIRT1) mRNA in metaphase II stage oocytes that were in vitro matured or collected from peri-ovulatory follicles. The frequency of aneuploidy and anomalies in spindle morphology was increased following IVM, along with a decrease in H4K16 acetylation that was in agreement with our previous observations. However, differences in the amount of the transcripts investigated were not detected. These results suggest that the degradation of transcripts encoding for histone deacetylases and acetyltransferases is not involved in the changes of H4K16 acetylation observed following IVM, while translational or post-translational mechanisms might have a role. Our study also suggests that epigenetic instabilities introduced by IVM may affect the oocyte and embryo genetic stability.
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    • "In mouse, the HORMA domain containing proteins, HORMAD1 and HORMAD2, are expressed in developing gonads with expression restricted to germ cells (Chen et al., 2005; Pangas et al., 2004; Shin et al., 2010). They localize specifically along unsynapsed chromosomes during meiotic prophase I (Fukuda et al., 2010). "
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    ABSTRACT: The HORMA domain was discovered in three chromatin-associated proteins in the budding yeast Saccharomyces cerevisiae. This domain has also been found in proteins with similar functions in organisms including plants, animals and nematodes. The HORMA domain containing proteins are thought to function as adaptors for meiotic checkpoint protein signaling and in the regulation of meiotic recombination. Surprisingly, new work has disclosed completely unanticipated and diverse functions for the HORMA domain containing proteins. A. M. Villeneuve and colleagues (2013) show that meiosis-specific HORMA domain containing proteins plays a vital role in preventing centriole disengagement during Caenorhabditis elegans spermatocyte meiosis. Another recent study reveals that S. cerevisiae Atg13 HORMA domain acts as a phosphorylation-dependent conformational switch in the cellular autophagic process.
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    • "scp2 and scp3, genes involved in synaptonemal complex formation, were recently found to be highly expressed in the maturing testis of the scallop Nodipecten subnodosus [6]. This synaptonemal complex is a meiosis-specific structure essential for chromosome pairing since disruption of the localization of scp2 and scp3 during early recombination resulting in aneuploidy [29]. Our results indicate that synaptonemal complex formation, and therefore meiosis I, was occurring from early to late testis maturation. "
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