Research Groups > Meiosis

Defects in meiosis lead to the generation of gametes carrying the wrong number of chromosomes, the leading cause of miscarriages and birth defects in humans. Correct chromosome partitioning during meiosis is achieved through a series of complex changes at the level of DNA molecules, chromosome structure and nuclear organization. A crucial aspect of meiosis is the formation of inter-homologue crossovers, which provide the basis of a temporary physical link that holds homologues together until they segregate from each other on the first meiotic spindle (Fig 1). Our main goal is to understand how the different events of meiosis are coordinated to ensure the orderly formation of inter-homologue crossovers.

Fig 1. Chromosome segregation during meiosis. A pair of homologues are represented in blue and red, sister chromatid cohesion is represented in yellow. During early meiotic prophase the homologues pair with each other and a proteinaceous structure, the synaptonemal complex (SC, purple lines) is assembled between them. Following SC disassembly, the chromosomes are remodeled around the crossover site, which provides the only linkage between the homologues at this stage. The selective release of sister chromatid cohesion during the meiotic division results in the formation of haploid gametes.
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To this end we are performing genetic screens designed to isolate mutants defective in crossover formation. Since C. elegans possesses six pairs of chromosomes, the presence in diakinesis nuclei (the stage before metaphase I) of more than six DAPI-stained bodies indicates defects in crossover formation (Fig 2). Mutants isolated in the screen are then analyzed with a combination of experimental approaches to determine the nature of the crossover defect.

Fig 2. Diakinesis nuclei stained with DAPI. (A) WT, six DAPI-stained bodies are present, demonstrating the presence of six chromosome pairs attached by crossovers. (B) htp-1 mutant, 12 unattached chromosomes present. (C) Mutant 318, unattached chromosomes plus small chromosome fragments (arrows).

We are also studying the interplay between crossovers and meiotic chromosome structure. We have shown that crossovers trigger a remodeling of chromosome axis composition that is required for proper homologue segregation, and that HTP-1, a protein associated with the axis of meiotic chromosomes, is a key player in this remodeling process (Fig 3). Studies are also directed at understanding the mechanisms that control the distribution of crossovers across the genome.

Fig 3. Chromosome remodeling during late meiotic prophase. All bivalents are stained with α-HTP-1 and α-SYP-1 (a synaptonemal complex component) antibodies, and DAPI. At the pachytene stage HTP-1 and SYP-1 co-localize along the whole length of the chromosomes. By late pachytene a clear boundary becomes visible between a HTP-1 depleted (SYP-1 enriched) domain and a HTP-1 enriched (SYP-1 depleted) domain. By diplotene chromosomes start coiling and the axial elements of the homologues are separated. By diakinesis HTP-1 is only present in the long arms of the bivalent and is missing from the mid-bivalent region, where SYP-1 remains present.