The Role of CENP-V in Mammalian Meiosis

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In somatic cells the group of W. Earnshaw showed that kinetochore protein CENP-V is involved in chromosome compaction, localization and stability of the chromosomal passenger complex (CPC), stable association of the cohesin protector SGO1 at centromeres, centromeric cohesion, metaphase plate alignment and proper chromosome segregation. However, CENP-V is very little described: there are only two reports on this protein, and nothing has been reported on CENP-V in meiosis, despite the central importance of the above listed chromosome properties for meiosis. We observed expression of CENP-V in mouse spermatocytes and oocytes and its specific chromosomal localization with enrichment at the pericentric heterochromatin and centromeres. Chromosome synapsis and presence of CENP-V correlate, CENP-V is largely absent from the unsynapsed X/Y chromatin, and it persists on desynapsing diplotene chromosomes. This suggest an association of CENP-V with synapsis. Most recently we obtained a mouse strain featuring spermatocyte-specific deficiency in CENP-V, which causes a drastic phenotype: the disappearance of the chromosome axes, the synaptonemal complexes (SCs). In cells with low CENP-V, the axes are shortened and appear either fragmented or unsynapsed. Based on our strongly supportive preliminary data, our hypothesis is that CENP-V plays one or several important roles during mammalian meiosis. We further hypothesize that the processes involving CENP-V partially differ between spermatocytes and oocytes. The latter is based on our observations that in spermatocytes CENP-V is specifically excluded from the X/Y chromatin. The initial analysis suggests that CENP-V is essential for synapsis-associated maintenance of chromosomal axes. This role will be analyzed. Whether CENP-V is required for proper cohesin association to chromosomes, proper centromere cohesion and segregation, CPC recruitment, are further questions to be addressed considering the relationship in somatic cells between cohesin, centromeres, CPC and CENP-V. Our specific aims are: 1. To determine the specific localization of CENP-V on spermatocyte and oocyte chromosomes and co-localization with diagnostic proteins throughout meiosis; 2. To define protein interaction partners of CENP-V in spermatocytes; 3. To decipher the function(s) in vivo of CENP-V, including the relationship to cohesin, in mouse oocytes and spermatocytes. With this program we expect to unravel the entirely unknown, yet apparently central role of CENP-V in mammalian meiosis.