Involvement of Nlrp5 in the Maintenance of Genome Integrity in Murine Oocytes

Nlrp5, a maternal-effect gene, is required for embryonic progression and female fertility in mice. Previous work indicated an age-related decline in Nlrp5 transcripts in murine oocytes. As maternal age is associated with increased spindle organization defects, studies in this thesis focused on the analysis of meiotic spindle defects in oocytes of Nlrp5-deficient mice. NALP5 protein showed a novel kinetochore-localization pattern, which was disturbed by spindle poisons. Nlrp5-deficient oocytes displayed a higher frequency of spindle abnormalities and chromosomal misalignment. Upon fertilization, these defects translated into increased incidences of multinucleation. As these phenotypes are associated with deficiencies in genome stability, we examined spindle assembly checkpoint (SAC) components. We found that numerous SAC proteins were dysregulated, implying that NALP5 may be critical in sensing oocyte-related SAC defects. We found that Nlrp5-deficient oocytes may have increased DNA damage. Thus, Nlrp5 may be an integral component responsible for preservation of genome integrity in female gametes.MAS