NLRP14 deficiency contributes to female infertility and early embryo arrest. NLRP14 deficiency contributes to female infertility and early embryo arrest

Oocyte maturation is vital to attain full competence required fertilization and embryogenesis. As a maternal effect factor, NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis is largely unknown. Whether NLRP14 deficiency accounts for human infertility with oocyte and embryo defects remains to be elucidated. Here, NLRP14 is identified essential for establishment of competent oocytes that can sustain early embryo development. Maternal deficiency of Nlrp14 results in sterility characterized by oocyte maturation defects and early embryo arrest. Nlrp14 ablation leads to compromised oocyte quality and developmental competence due to impaired oocyte cytoplasmic and nuclear maturation. Mechanistically, NLRP14 interacts with UHRF1 in oocyte cytoplasm to protect it from proteasome-dependent degradation, and perturbs maternal mRNA zygotic-decay and zygotic genome activation during maternal-zygotic transition. Furthermore, compound heterozygous pathogenic variants in NLRP14 gene are identified in infertile women with early embryonic arrest, which interrupt the NLRP14-UHRF1 interaction or UHRF1 protein expression. Our data uncover a vital role of NLRP14 as a new cytoplasmic-specific modulator of UHRF1 in oocyte meiotic maturation and early embryogenesis, which should provide new insights into risk prediction and genetic diagnosis for female infertility. Overall design: We performed RNA-seq of oocytes and embryos of wild type and Nlrp14 knockout mice at four stages to obtain and analyze the gene expression profiles.

卵母细胞成熟对于获取受精与胚胎发生所需的完全发育能力至关重要。作为母源效应因子，NLRP14在哺乳动物卵母细胞与早期胚胎中呈优先表达状态。然而，NLRP14在卵母细胞成熟及早期胚胎发生中的作用与分子机制在很大程度上仍未明确，而NLRP14缺陷是否会导致伴卵母细胞与胚胎缺陷的人类不孕症，仍有待阐明。
本研究证实，NLRP14对于建立具备支持早期胚胎发育潜能的卵母细胞是必需的。母源Nlrp14缺失会引发不育，其特征为卵母细胞成熟缺陷与早期胚胎阻滞。Nlrp14敲除会因卵母细胞胞质与核成熟受损，导致卵母细胞质量与发育能力下降。
从机制层面而言，NLRP14可在卵母细胞胞质中与UHRF1相互作用，从而保护其免受蛋白酶体依赖性降解，并干扰母源-合子转变过程中的母源mRNA的合子降解以及合子基因组激活。
此外，我们在伴早期胚胎阻滞的不孕女性患者中鉴定出了NLRP14基因的复合杂合致病性变异，此类变异会破坏NLRP14与UHRF1的相互作用或影响UHRF1蛋白的表达。
本研究揭示了NLRP14作为一种新型胞质特异性调控因子，在卵母细胞减数分裂成熟及早期胚胎发生中对UHRF1的调控作用，这将为女性不孕症的风险预测与遗传学诊断提供全新的研究视角。
总体实验设计：我们对四个发育阶段的野生型与Nlrp14敲除小鼠的卵母细胞及胚胎进行了RNA测序（RNA-seq），以获取并分析基因表达谱。