MiR-202 controls female fecundity by regulating medaka oogenesis

International audienceFemale gamete production relies on coordinated molecular and cellular processes thatoccur in the ovary throughout oogenesis. In fish, as in other vertebrates, these processeshave been extensively studied both in terms of endocrine/paracrine regulation and proteinexpression and activity. The role of small non-coding RNAs in the regulation of animal reproductionremains however largely unknown and poorly investigated, despite a growinginterest for the importance of miRNAs in a wide variety of biological processes. Here, weanalyzed the role of miR-202, a miRNA predominantly expressed in male and femalegonads in several vertebrate species. We studied its expression in the medaka ovary andgenerated a mutant line (using CRISPR/Cas9 genome editing) to determine its importancefor reproductive success with special interest for egg production. Our results show that miR-202-5p is the most abundant mature form of the miRNA and that it is expressed in granulosacells and in the unfertilized egg. The knock out (KO) of mir-202 gene resulted in a strongphenotype both in terms of number and quality of eggs produced. Mutant females exhibitedeither no egg production or produced a dramatically reduced number of eggs that could notbe fertilized, ultimately leading to no reproductive success. We quantified the size distributionof the oocytes in the ovary of KO females and performed a large-scale transcriptomicanalysis approach to identified dysregulated molecular pathways. Together, cellular andmolecular analyses indicate that the lack of miR-202 impairs the early steps of oogenesis/folliculogenesis and decreases the number of large (i.e. vitellogenic) follicles, ultimatelyleading to dramatically reduced female fecundity. This study sheds new light on the regulatorymechanisms that control the early steps of follicular development, including possibletargets of miR-202-5p, and provides the first in vivo functional evidence that a gonad-predominantmicroRNA may have a major role in female reproduction