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Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)‐binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock‐in (KI) female mice were infertile. RNA‐sequencing analysis showed abnormal activation of the Mos‐MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility. Synopsis: Seven rare variants in PABPC1L were identified in five infertile females mainly characterized by oocyte maturation arrest followed recessive inheritance pattern. In vitro and in vivo functional studies confirmed the destructive effects and pathogenicity of PABPC1L variants. In vitro, truncating variants resulted in truncated proteins, reduced protein abundance, and altered cytoplasmic localization.Missense variants impaired the ability of RNA‐binding and mRNA translational activation of PABPC1L protein.In vivo, three strains of Pabpc1l KI mice corresponding to patient‐derived variants showed early embryonic arrest and female infertility.Mos‐MAPK pathway was abnormally activated in KI zygotes and the phenotype of KI mice was mimicked by injecting MOS mRNA into the zygotes. [ABSTRACT FROM AUTHOR]

Abstract Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)‐binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock‐in (KI) female mice were infertile. RNA‐sequencing analysis showed abnormal activation of the Mos‐MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility.

Oocytes are arrested in prophase I. In vertebrates, meiotic resumption is triggered by hormonal stimulation that results in cAMP-dependent protein kinase (PKA) downregulation leading to Cdk1 activation. Yet the pathways connecting PKA to Cdk1 remain unclear. Here, we identify molecular events triggered by PKA downregulation occurring upstream of Cdk1 activation. We describe a two-step regulation controlling cyclin B1 and Mos accumulation, which depends on both translation and stabilization. Cyclin B1 accumulation is triggered by PKA inhibition upstream of Cdk1 activation, while its translation requires Cdk1 activity. Conversely, Mos translation initiates in response to the hormone, but the protein accumulates only downstream of Cdk1. Furthermore, two successive translation waves take place, the first controlled by PKA inhibition and the second by Cdk1 activation. Notably, Arpp19, an essential PKA effector, does not regulate the early PKA-dependent events. This study elucidates how PKA downregulation orchestrates multiple pathways that converge toward Cdk1 activation and induce the oocyte G2/M transition. [Display omitted] • Multiple molecular pathways connect PKA downregulation to Cdk1 activation • Cyclin B1 and Mos accumulation is opposingly controlled by a two-step mechanism • Two waves of translation occur during the G2/M transition Santoni et al. identify multiple pathways connecting PKA downregulation to Cdk1 activation and controlling G2/M transition in oocytes. Among the events taking place upstream of Cdk1 activation, they highlight the interplay between protein translation and stabilization in controlling the accumulation of critical cell-cycle regulators, including Mos and cyclin B1. [ABSTRACT FROM AUTHOR]

Maintenance of spindle attachment to the cortex and formation of the cleavage furrow around the protruded spindle are essential for polar body extrusion (PBE) during meiotic maturation of oocytes. Although spindle movement to the cortex has been well-studied, how the spindle is maintained at the cortex during PBE is unknown. Here, we show that activation of Diaphanous-related formin mediated by mitogen-activated protein kinase (MAPK) is required for tight spindle attachment to the cortex and cleavage furrow closure during PBE in starfish (Asterina pectinifera) oocytes. A. pectinifera Diaphanous-related formin (ApDia) had a distinct localization in immature oocytes and was localized to the cleavage furrow during PBE. Inhibition of the Mos-MAPK pathway or the actin nucleating activity of formin homology 2 domain prevented cleavage furrow closure and resulted in PBE failure. In MEK/MAPK-inhibited oocytes, activation of ApDia by relief of its intramolecular inhibition restored PBE. In summary, this study elucidates a link between the Mos-MAPK pathway and Diaphanous-related formins, that is responsible for maintaining tight spindle attachment to the cortex and cleavage furrow closure during PBE. [ABSTRACT FROM AUTHOR]