Figure 8. Model for meiotic progression: negative feedback-loop of HORMAD1 and SC coordinates homology search and meiotic progression.

Processes, activation-promotion and inhibition are marked by continuous black arrows, red dashed arrows and blue flat-ended dashed arrows, respectively. HORMAD1 associates with forming chromosome axes at the beginning of meiosis where it promotes DSB formation and/or processing of DSBs. It thereby ensures that adequate numbers of single-stranded DSBs are available for homology search. As part of the homology search process DSB ends strand-invade into homologues. Multiple strand invasion events along the length of chromosomes lead to full alignment of pairs of homologues, which is a prerequisite for the completion of SC formation. HORMAD1 also promotes SC formation through a mechanism that is independent of homology search. SC formation leads to depletion of HORMAD1 from axes and down-regulation of HORMAD1 function⁴⁰. Hence, in spermatocytes, full autosomal SC formation leads to a restriction of HORMAD1 and ATR activity to sex chromosomes, thereby promoting efficient silencing of sex chromosomes, which is a prerequisite for progression beyond mid-pachytene¹³, ⁶⁰, ⁶¹. In oocytes, completion of SC formation on all chromosomes leads to complete inactivation of HORMAD1, which in turn leads to down-regulation of ATR and MSUC. Since sustained ATR activity and/or sustained MSUC is believed to block progression beyond meiotic prophase¹³, full SC formation and HORMAD1 inactivation link successful homologue alignment with progression beyond meiotic prophase. Note that successful DSB repair is probably also required for full down-regulation of ATR activity and for meiotic progression in oocytes (for the sake of simplicity, this branch of the prophase checkpoint is not displayed in the model).