HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity

Genes Cells. 2012 Nov;17(11):897-912. doi: 10.1111/gtc.12005. Epub 2012 Oct 8.


Meiotic chromosome segregation requires homologous pairing, synapsis and crossover recombination during meiotic prophase. The checkpoint kinase ATR has been proposed to be involved in the quality surveillance of these processes, although the underlying mechanisms remain largely unknown. In our present study, we generated mice lacking HORMAD2, a protein that localizes to unsynapsed meiotic chromosomes. We show that this Hormad2 deficiency hampers the proper recruitment of ATR activity to unsynapsed chromosomes. Male Hormad2-deficient mice are infertile due to spermatocyte loss as a result of characteristic impairment of sex body formation; an ATR- and γH2AX-enriched repressive chromatin domain is formed, but is partially dissociated from the elongated sex chromosome axes. In contrast to males, Hormad2-deficient females are fertile. However, our analysis of Hormad2/Spo11 double-mutant females shows that the oocyte number is negatively correlated with the frequency of pseudo-sex body formation in a Hormad2 gene dosage-dependent manner. This result suggests that the elimination of Spo11-deficient asynaptic oocytes is associated with the HORMAD2-dependent pseudo-sex body formation that is likely initiated by local concentration of ATR activity in the absence of double-strand breaks. Our results thus show a HORMAD2-dependent quality control mechanism that recognizes unsynapsis and recruits ATR activity during mammalian meiosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology*
  • Chromosome Pairing*
  • DNA Breaks, Double-Stranded
  • Endodeoxyribonucleases / deficiency
  • Endodeoxyribonucleases / genetics
  • Female
  • Fertility / genetics
  • Gene Silencing
  • Male
  • Meiotic Prophase I
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • Oocytes / metabolism
  • Oocytes / physiology
  • Ovary / cytology
  • Ovary / enzymology
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Spermatocytes / metabolism
  • Spermatocytes / physiology
  • Testis / cytology


  • BRCA1 Protein
  • Cell Cycle Proteins
  • HORMAD2 protein, mouse
  • Nohma protein, mouse
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Endodeoxyribonucleases
  • meiotic recombination protein SPO11