title: Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Shin
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.forename: Serpil Uckac
authors.initials: SU
authors.lastname: Erdin
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kloc
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: Wang
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Meistrich
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rajkovic
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010053:Ovary / Q000254:growth & development / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics*; D012730:Sex Chromosomes / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D013573:Synaptonemal Complex / Q000378:metabolism* / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C506693:Nohma protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases