Wdr62 is involved in female meiotic initiation via activating JNK signaling and associated with POI in humans

Yang Zhou; Yan Qin; Yingying Qin; Binyang Xu; Ting Guo; Hanni Ke; Min Chen; Lianjun Zhang; Feng Han; Yaqiong Li; Min Chen; Axel Behrens; Yaqing Wang; Zhiheng Xu; Zi-Jiang Chen; Fei Gao

doi:10.1371/journal.pgen.1007463

Wdr62 is involved in female meiotic initiation via activating JNK signaling and associated with POI in humans

PLoS Genet. 2018 Aug 13;14(8):e1007463. doi: 10.1371/journal.pgen.1007463. eCollection 2018 Aug.

Authors

Yang Zhou^{1

2}, Yan Qin^{1

2}, Yingying Qin³, Binyang Xu^{1

2}, Ting Guo³, Hanni Ke³, Min Chen¹, Lianjun Zhang^{1

2}, Feng Han^{1

2}, Yaqiong Li^{1

2}, Min Chen^{1

2}, Axel Behrens⁴, Yaqing Wang⁵, Zhiheng Xu⁵, Zi-Jiang Chen³, Fei Gao^{1

2}

Affiliations

¹ State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Center for Reproductive Medicine of Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
⁴ CR-UK London Research Institute, London, United Kingdom.
⁵ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.

Abstract

Meiosis is a germ cell-specific division that is indispensable for the generation of haploid gametes. However, the regulatory mechanisms of meiotic initiation remain elusive. Here, we report that the Wdr62 (WD40-repeat protein 62) is involved in meiotic initiation as a permissive factor rather than an instructive factor. Knock-out of this gene in a mouse model resulted in female meiotic initiation defects. Further studies demonstrated that Wdr62 is required for RA-induced Stra8 expression via the activation of JNK signaling, and the defects in meiotic initiation from Wdr62-deficient female mice could be partially rescued by JNK1 overexpression in germ cells. More importantly, two novel mutations of the WDR62 gene were detected in patients with premature ovarian insufficiency (POI), and these mutations played dominant-negative roles in regulating Stra8 expression. Hence, this study revealed that Wdr62 is involved in female meiotic initiation via activating JNK signaling, which displays a novel mechanism for regulating meiotic initiation, and mutation of WDR62 is one of the potential etiologies of POI in humans.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Asian People / genetics
Cell Cycle Proteins / deficiency
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Disease Models, Animal
Exome Sequencing
Female
Gene Deletion
Gene Expression Regulation
Germ Cells
Haploidy
Humans
MAP Kinase Signaling System / genetics*
Meiosis
Mice
Mice, Knockout
Microtubule-Associated Proteins / deficiency
Microtubule-Associated Proteins / genetics*
Microtubule-Associated Proteins / metabolism
Nerve Tissue Proteins / deficiency
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Primary Ovarian Insufficiency / diagnosis
Primary Ovarian Insufficiency / genetics*
Sequence Analysis, DNA

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Microtubule-Associated Proteins
Nerve Tissue Proteins
STRA8 protein, human
Stra8 protein, mouse
WDR62 protein, human
WDR62 protein, mouse

Grants and funding

This work was supported by National key R&D program of China (2016YFA0500901); The National Science Fund for Distinguished Young Scholars (81525011); Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000); The National Natural Science Foundation of China (31471348, 31601193, and 31671496). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.