Mouse HFM1/Mer3 Is Required for Crossover Formation and Complete Synapsis of Homologous Chromosomes during Meiosis

Abstract

Faithful chromosome segregation during meiosis requires that homologous chromosomes associate and recombine. Chiasmata, the cytological manifestation of recombination, provide the physical link that holds the homologs together as a pair, facilitating their orientation on the spindle at meiosis I. Formation of most crossover (CO) events requires the assistance of a group of proteins collectively known as ZMM. HFM1/Mer3 is in this group of proteins and is required for normal progression of homologous recombination and proper synapsis between homologous chromosomes in a number of model organisms. Our work is the first study in mammals showing the in vivo function of mouse HFM1. Cytological observations suggest that initial steps of recombination are largely normal in a majority of Hfm1 ^−/− spermatocytes. Intermediate and late stages of recombination appear aberrant, as chromosomal localization of MSH4 is altered and formation of MLH1foci is drastically reduced. In agreement, chiasma formation is reduced, and cells arrest with subsequent apoptosis at diakinesis. Our results indicate that deletion of Hfm1 leads to the elimination of a major fraction but not all COs. Formation of chromosome axial elements and homologous pairing is apparently normal, and Hfm1 ^−/− spermatocytes progress to the end of prophase I without apparent developmental delay or apoptosis. However, synapsis is altered with components of the central region of the synaptonemal complex frequently failing to extend the full length of the chromosome axes. We propose that initial steps of recombination are sufficient to support homology recognition, pairing, and initial chromosome synapsis and that HFM1 is required to form normal numbers of COs and to complete synapsis.

Author Summary

Meiosis is a specialized type of cell division during which haploid gametes are generated to offset doubling of the chromosome number that occurs at fertilization. Prior to segregation in the first meiotic division, meiotic chromosomes pair and recombine. Chiasmata, products of recombination, provide the temporary physical link between the chromosomes of each pair. This association is required to prepare the chromosomes for segregation to the opposite poles of the spindle at the first meiotic division, so that ultimately each gamete receives only one copy of each chromosome. For this reason, errors in recombination are commonly linked to human infertility, spontaneous abortions, and severe aneuploid-based birth defects. We observed that the absence of HFM1/Mer3 results in deficient recombination and in incomplete meiosis-specific modification of chromosome structure. Our findings thus indicate that the mouse HFM1 protein is required for normal progression of important aspects of meiosis that act to insure that the correct numbers of chromosomes are transferred to the next generation.