NEDD1 is crucial for meiotic spindle stability and accurate chromosome segregation in mammalian oocytes

Abstract

Defects in meiotic spindle structure contribute to chromosome segregation errors leading to genomic instability in oocytes and embryos upon fertilization. In this study, we analyzed the mechanisms that control spindle microtubule nucleation and stability in mammalian oocytes, and identified NEDD1/GCP-WD as a key regulator. NEDD1 specifically co-localizes with gamma-tubulin and pericentrin at microtubule-organizing centers (MTOCs) in mouse oocytes arrested at prophase-I. During metaphase-I and metaphase-II, the protein remains associated with MTOCs, in a pericentrin dependent manner. Notably, knockdown of Nedd1 transcripts using specific siRNAs resulted in a high incidence (65-70%) of metaphase-I arrest. The arrested oocytes were characterized by disrupted meiotic spindle structure, reduced microtubule density and significant chromosome misalignment. Detection of MAD2 at kinetochores indicated an absence of stable chromosome-microtubule attachment as well as activation of the spindle assembly checkpoint (SAC). Importantly, the disruption of meiotic spindle stability was associated with decreased gamma-tubulin at MTOCs in NEDD1-depleted oocytes, as well as a high frequency of chromosome non-disjunction errors leading to aneuploidy (50%) in the oocytes that did progress to metaphase-II. This study demonstrates that NEDD1 is an essential component of acentriolar oocyte MTOCs, which functions in the regulation of meiotic spindle stability. Moreover, it underscores that disruption of spindle stability in oocytes can lead to chromosomes segregation errors that are not fully resolved by SAC.