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Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis

Shin, YH and Choi, Y and Erdin, SU and Yatsenko, SA and Kloc, M and Yang, F and Wang, PJ and Meistrich, ML and Rajkovic, A (2010) Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis. PLoS Genetics, 6 (11). ISSN 1553-7390

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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 cH2AX 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. © 2010 Shin et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Shin, YH
Choi, Y
Erdin, SU
Yatsenko, SA
Kloc, M
Yang, F
Wang, PJ
Meistrich, ML
Rajkovic, Aalr110@pitt.eduALR110
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 November 2010
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 6
Number: 11
DOI or Unique Handle: 10.1371/journal.pgen.1001190
Refereed: Yes
ISSN: 1553-7390
MeSH Headings: Aneuploidy; Animals; Cell Cycle Proteins--genetics; Cell Cycle Proteins--metabolism; Chromosome Segregation--genetics; DNA-Binding Proteins--metabolism; Embryonic Development--genetics; Female; Fetus--cytology; Fetus--metabolism; Male; Meiosis--genetics; Mice; Mutation--genetics; Nuclear Proteins--metabolism; Oocytes--cytology; Oocytes--metabolism; Organ Specificity--genetics; Ovary--growth & development; Ovary--metabolism; Phosphorylation; Protein Transport; Protein-Serine-Threonine Kinases--metabolism; RNA, Messenger--genetics; RNA, Messenger--metabolism; Recombination, Genetic--genetics; Sex Chromosomes--genetics; Spermatogenesis--genetics; Spermatozoa--cytology; Spermatozoa--metabolism; Spermatozoa--ultrastructure; Synaptonemal Complex--metabolism; Synaptonemal Complex--ultrastructure; Tumor Suppressor Proteins--metabolism
Other ID: NLM PMC2973818
PubMed Central ID: PMC2973818
PubMed ID: 21079677
Date Deposited: 22 Aug 2012 21:55
Last Modified: 22 Jun 2021 15:55


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