Meiosis is a specialized cell division program resulting in the production of haploid gametes (eggs and sperm) from diploid germ cells. Errors in achieving accurate chromosome segregation during meiosis can result in infertility, miscarriages and birth defects such as Down syndrome. Therefore, understanding the mechanisms underlying accurate meiotic chromosome segregation is of tremendous importance for human reproductive health. Here, we uncovered a role for GRAS-1, the worm homolog of mammalian GRASP and CYTIP proteins, in coordinating early meiotic events with cytoskeletal forces outside the nucleus. GRAS-1/GRASP/CYTIP contains PDZ and coiled-coil domains and in mammals has been implicated in docking cytoskeleton components and in endosomal trafficking. A role for GRAS-1/GRASP/CYTIP during meiosis has not been previously demonstrated. gras-1 expression starts upon entrance into meiosis and GRAS-1 localizes in close proximity to the nuclear envelope (NE)-associated protein SUN-1 starting at early prophase I. GRAS-1 IPs and MS analysis reveal it interacts with other NE and cytoskeleton proteins. gras-1 mutants show an extended transition zone (leptotene/zygotene stage), a delay in achieving homologous pairing, the formation of aggregates with SC central region proteins that persist into pachytene while chromosome axes appear unaltered, and impaired DNA double-strand break repair progression. Importantly, these defects are partially rescued by expression of mammalian CYTIP in gras-1 mutants, supporting functional conservation. These defects likely stem from a role for GRAS-1 in regulating chromosome dynamics given that gras-1 mutants show accelerated chromosome movement during early prophase I. Moreover, in a dhc-1 depleted background, gras-1 mutants exhibit new and additional phenotypes, indicating that gras-1 regulation of chromosome movement acts in parallel to the previously described LINC-controlled pathway. Finally, GRAS-1 undergoes phosphorylation, and analysis of a phosphodead mutant reveals that this post-translational modification is required for regulating GRAS-1 function during meiosis. We propose that GRAS-1 serves as a scaffold for a multi-protein complex coordinating the early steps of homolog search and licensing of SC assembly by regulating the pace of chromosome movement in early prophase I.

Authors: Martinez-Garcia, Marina, Robles Naharro, Pedro, Nadarajan, Saravanapriah, Shin, Nara, Silva-Garcia, Carlos G., Saito, Takamune, Beese-Sims, Sara, Castaner, Ana, Martinez-Perez, Enrique, Colaiacovo, Monica P.

Affiliations:
- MRC London Institute of Medical Sciences, London W12 0NN, UK
- Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.