A Defective Meiotic Outcome of a Failure in Homologous Pairing and Synapsis Is Masked by Meiotic Quality Control

Abstract

Successful gamete production is ensured by meiotic quality control, a process in which germ cells that fail in bivalent chromosome formation are eliminated during meiotic prophase. To date, numerous meiotic mutants have been isolated in a variety of model organisms, using defects associated with a failure in bivalent formation as hallmarks of the mutant. Presumably, the meiotic quality control mechanism in those mutants is overwhelmed. In these mutants, all germ cells fail in bivalent formation, and a subset of cells seem to survive the elimination process and develop into gametes. It is possible that mutants that are partially defective in bivalent formation were missed in past genetic screens, because no evident meiotic defects associated with failure in bivalent formation would have been detectable. Meiotic quality control effectively eliminates most failed germ cells, leaving predominately successful ones. Here, we provide evidence supporting this possibility. The Caenorhabditis elegans mrg-1 loss-of-function mutant does not appear to be defective in bivalent formation in diakinesis oocytes. However, defects in homologous chromosome pairing and synapsis during the preceding meiotic prophase, prerequisites for successful bivalent formation, were observed in most, but not all, germ cells. Failed bivalent formation in the oocytes became evident once meiotic quality control was abrogated in the mrg-1 mutant. Both double-strand break repair and synapsis checkpoints are partly responsible for eliminating failed germ cells in the mrg-1 mutant. Interestingly, removal of both checkpoint activities from the mrg-1 mutant is not sufficient to completely suppress the increased germline apoptosis, suggesting the presence of a novel meiotic checkpoint mechanism.

Phospho-Regulation of Meiotic Prophase

“…Many organisms delay meiotic progression in response to problems in meiotic DSB repair or defects in chromosome synapsis. These delays are similar to the cell-cycle delays observed in the canonical DNA-damage response and help to ensure that cells do not initiate the meiotic divisions with broken chromosomes (Mei et al, 2015;ElInati et al, 2020). The pachytene checkpoint employs the canonical DNA-damage sensor kinases ATR and ATM in most organisms (Hochwagen and Amon, 2006;Subramanian and Hochwagen, 2014).…”

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

“…In some instances, meiotic quality control mechanisms have been reported to mask nearly all errors, thereby drastically improving gamete quality (Mei et al, 2015). In spite of this, activation of the recombination/DDR checkpoints alone are not sufficient to eliminate all defective nuclei.…”

“…Given that an absence of viable, aneuploid offspring can be masked by high levels of apoptosis (Mei et al, 2015), we also performed cytological analyses to probe Mi2 deficient germlines for defects that could impact HR. We monitored synaptonemal complex (SC) loading in let-418(n3536) and chd-3(eh4) mutants, both singly and in combination.…”