Abstract
PAT1 homolog 2 (PATL2), encoding an RNA-binding protein, is a repressor involved in the translational regulation of maternal mRNAs during oocyte maturation. Previous studies have reported mutations in PATL2 those led to female infertility with oocyte maturation arrest; however, the mechanisms by which mutations affected meiotic maturation remained unclear. Here, we identified several novel and recurrent mutations of PATL2 in patients with similar phenotype, and chose the missense mutation c.649 T>A p.Tyr217Asn in PATL2 (PATL2Y217N) as a typical to investigate the underlying mechanisms. We confirmed that this mutation disturbed oocyte maturation and observed morphological defects of large polar body, symmetrical division and abnormal spindle after microinjection of corresponding mutated mRNA. We further evaluated the effect of the PATL2Y217N mutation in 293T cells, and found this mutation decreased the ubiquitination level and degradation of PATL2. Then, abnormally increased PATL2 bound mRNAs of Mos, an upstream activator of mitogen activated protein kinase (MAPK), to regulate its translational activity and subsequently impaired MAPK signaling pathway and oocyte meiosis. These results dissented from the previous view that PATL2 mutations reduced their expression and highlight the role of PATL2 in translational regulation of Mos and its association with MAPK signaling pathway during oocyte meiotic maturation.
Highlights
The wide application of assisted reproductive technology (ART) allows us to access the maturity and classify phenotypes based on the morphology of oocytes upon retrieval (Ebner et al, 2003; Muasher et al, 2006; Beall et al, 2010)
The severe phenotype of impaired meiosis in PAT1 homolog 2 (PATL2) mutation group could be rescued to some extent indicated by the increased Pb1 extrusion rate (Figures 5E,F). These findings demonstrate that in oocytes, PATL2 is important for the proper translation of MOS and the activation of mitogen activated protein kinase (MAPK) signaling pathway
Previous studies have reported that PATL2 mutations are responsible for oocyte maturation arrest at germinal vesicle (GV) stage and several slightly variable phenotypes (Chen et al, 2017b; Maddirevula et al, 2017; Huang et al, 2018)
Summary
The wide application of assisted reproductive technology (ART) allows us to access the maturity and classify phenotypes based on the morphology of oocytes upon retrieval (Ebner et al, 2003; Muasher et al, 2006; Beall et al, 2010). Cytoplasmic polyadenylation element binding protein 1 (CPEB1) is a key regulator for maternal mRNA translation but undergoes ubiquitin-dependent degradation during meiosis I otherwise it can affect the progression to meiosis II (Setoyama et al, 2007; Ivshina et al, 2014). In this respect, protein degradation may be viewed as a prerequisite to complete the oocyte maturation and achieve oocyte-to-zygote transition. Any subtle defect in these procedures could result in maturation failure
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