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.
Highlights
In mammals, the haploid gametes are generated via meiosis, a program of two successive cell divisions preceded by one round of DNA replication
Meiosis is a unique cell division process which is indispensable for the generation of haploid gametes
We demonstrated that Wdr62 is required for female meiotic initiation in germ cells via activating JNK signaling
Summary
The haploid gametes are generated via meiosis, a program of two successive cell divisions preceded by one round of DNA replication. The onset of this program is referred to as meiotic initiation. RA induces the germ cells to express the gatekeeper gene of meiosis Stra (stimulated by retinoic acid gene 8) [3]. The molecular functions of Stra have not yet been identified, several studies have shown that it is the first detectable sign of a germ cell’s decision to enter meiosis and is essential for pre-meiotic DNA replication and subsequent meiotic initiation [4,5,6]. The RNA-binding protein DAZL (deleted in azoospermia-like) is an intrinsic factor required for germ cells to initiate the process of meiosis. The morphological changes during meiosis have been extensively studied, the underlying mechanisms that initiate this process remain largely unknown
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