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Foxl3, a Sexual Switch in Germ Cells, Initiates Two Independent Molecular Pathways for Commitment to Oogenesis in Medaka

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Foxl3, a Sexual Switch in Germ Cells, Initiates Two Independent Molecular Pathways for Commitment to Oogenesis in Medaka foxl3, a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka Mariko Kikuchia, Toshiya Nishimuraa,1, Satoshi Ishishitab, Yoichi Matsudab,c, and Minoru Tanakaa,2 aDivision of Biological Science, Graduate School of Science, Nagoya University, 464-8602 Nagoya, Japan; bAvian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University, 464-8601 Nagoya, Japan; and cDepartment of Animal Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, 464-8601 Nagoya, Japan Edited by John J. Eppig, The Jackson Laboratory, Bar Harbor, ME, and approved April 8, 2020 (received for review October 23, 2019) Germ cells have the ability to differentiate into eggs and sperm and elegans (8–10). To date, however, neither protein has been im- must determine their sexual fate. In vertebrates, the mechanism of plicated in germline feminization. commitment to oogenesis following the sexual fate decision in During oogenesis in mice, several transcription factors facili- germ cells remains unknown. Forkhead-box protein L3 (foxl3)isa tate folliculogenesis: lhx8 (LIM homeobox 8) and figla (factor in switch gene involved in the germline sexual fate decision in the the germline alpha) regulate differentiation of primordial follicles teleost fish medaka (Oryzias latipes). Here, we show that foxl3 or- (11–14), and nobox (newborn ovary homeobox), which acts ganizes two independent pathways of oogenesis regulated by REC8 downstream of Lhx8, is indispensable for the formation of sec- meiotic recombination protein a (rec8a), a cohesin component, and ondary follicles (12, 15). It remains unknown how these tran- F-box protein (FBP)47(fbxo47), a subunit of E3 ubiquitin ligase. In scription factors cooperate after sexually indifferent germ cells mutants of either gene, germ cells failed to undergo oogenesis but commit to oogenesis. developed normally into sperm in testes. Disruption of rec8a Here, we show that foxl3 orchestrates two independent path- resulted in arrest at a meiotic pachytenelike stage specifically in ways for oogenesis: one leading to meiosis by rec8a and the other females, revealing a sexual difference in meiotic progression. to follicle development by fbxo47. In addition, we show that the Analyses of fbxo47 mutants showed that this gene regulates tran- fbxo47-downstream pathway ensures that germ cells do not de- DEVELOPMENTAL BIOLOGY scription factors that facilitate folliculogenesis: LIM homeobox 8 viate from the oogenesis pathway during early meiotic prophase α (lhx8b), factor in the germline (figla), and newborn ovary ho- I; otherwise, the sexual fate of the germ cells would change to meobox (nobox). Interestingly, we found that the fbxo47 pathway spermatogenesis. Thus, we propose that the diplotene stage of ensures that germ cells do not deviate from an oogenic pathway meiotic prophase I is the point of no return for establishing until they reach diplotene stage. The mutant phenotypes together germline feminization. with the timing of their expression imply that germline feminiza- tion is established during early meiotic prophase I. Results rec8a Is Required for Female Meiotic Progression. To investigate the germline sex determination | foxl3 | rec8a | fbxo47 | oogenesis function of rec8a in germline feminization, we generated rec8a commitment Significance erm cells, which have the potential to differentiate into eggs and sperm, must determine their sexual fate. In the teleost G In teleost fish, unlike mammals, retinoic acid (RA) does not exert fish medaka (Oryzias latipes), the onset of the germline sexual a conspicuous feminization effect of germ cells. Instead, in the fate decision is triggered by foxl3 (forkhead box protein L3) (1). teleost fish medaka, foxl3 serves as a germ cell-autonomous During medaka gonadal development, foxl3 expression is main- factor acting at the very beginning of the sexual fate decision. tained only in female germ cells, and the loss-of-function mutant This study shows that foxl3 initiates oogenesis through two of foxl3 results in production of functional sperm in the ovary, genetically independent pathways, meiosis and follicular devel- indicating that foxl3 is required for suppression of spermatogenesis opment. One pathway, involving rec8a, drives female-specific in female germ cells (1). However, the specific role of foxl3 in regulation of meiosis. The other, involving fbxo47, both directs germline feminization (process of commitment to oogenesis) has follicular development and suppresses spermatogenesis com- not been clarified. mitment. The involvement of two evolutionarily conserved fac- To elucidate the molecular pathways organized by foxl3,we tors in oogenesis suggests the existence of an RA-independent previously identified rec8a (REC8 meiotic recombination protein pathway that promotes oogenesis, common in vertebrates. In a) and fbxo47 (F-box protein 47) as direct targets of FOXL3 (2). addition, our findings reveal the timing of the establishment of rec8a and fbxo47 transcripts are detected in mitotic germ cells − − germ cell feminization. expressing foxl3 in wild-type ovaries but not in foxl3 / ovaries and are indicated to act downstream of foxl3 during germline sex Author contributions: M.K. and M.T. designed research; M.K., T.N., and S.I. performed determination (2). rec8a is one of two Rec8 orthologs resulting research; T.N. contributed new reagents/analytic tools; M.K., S.I., Y.M., and M.T. analyzed from the teleost-specific whole-genome duplication (3). REC8 is data; and M.K. and M.T. wrote the paper. a meiosis-specific kleisin subunit of the cohesin complex, which The authors declare no competing interest. plays crucial roles in various meiosis-associated chromosomal This article is a PNAS Direct Submission. events, including chromosomal axis formation and homolog as- Published under the PNAS license. sociation (4). Rec8-null mutant mice of both sexes are sterile and 1Present address: Division of Marine Life Science, Graduate School of Fisheries Sciences, fail to complete meiotic prophase I (5, 6). On the other hand, the Hokkaido University, 041-8611 Hakodate, Japan. F-box domain-containing protein FBXO47 has been implicated 2To whom correspondence may be addressed. Email: [email protected]. to act as a subunit of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin This article contains supporting information online at https://www.pnas.org/lookup/suppl/ ligases (7). Notably, germ cells in the fbxo47 mutant exhibit de- doi:10.1073/pnas.1918556117/-/DCSupplemental. fects in meiotic recombination in both mice and Caenorhabditis www.pnas.org/cgi/doi/10.1073/pnas.1918556117 PNAS Latest Articles | 1of8 Downloaded by guest on September 23, 2021 − − mutants by CRISPR/Cas9 (SI Appendix, Fig. S1). rec8a / XY fbxo47 mutants was similar to that observed in wild-type sper- males developed normal testes with mature sperm (SI Appendix, matogenesis (Fig. 2 C, Bottom, and SI Appendix, Fig. S4H). Fig. S2 A and B). Although the hatching rate of eggs fertilized To test the hypothesis that fbxo47-mutant germ cells committed − − with rec8a / XY sperm was slightly lower than that of eggs with to spermatogenesis, we examined the expression of shippo1b,a − − wild-type sperm, rec8a / XY sperm were fertile (SI Appendix, spermatocyte and spermatid marker, by in situ hybridization. The − − Fig. S2 C and D). On the other hand, rec8a / XX females were shippo1b signal was detected in both the control wild-type XY sterile, and all of the mutant ovaries lacked follicles (Fig. 1 A and testes and the fbxo47-mutant XX ovaries (Fig. 2 D and E). − − B). Because we could not find germ cells at the diplotene stage in Interestingly, shippo1b was already expressed in fbxo47 / XX the mutant ovaries, meiosis was likely arrested before the dip- gonads at 15 days posthatching (dph), consistent with the time − − lotene stage (Fig. 1 A and B, Insets). when spermatogenesis initiated in the foxl3 / XX gonads (1) We next examined the synaptonemal complex (SC) formation (Fig. 2 F and G and SI Appendix,Fig.S5). −/− +/− in rec8a ovaries. In the control (rec8a ) ovaries, synapsis To further analyze the function of fbxo47, we introduced a marker SYCP1 (a central element of SC) localized between ho- bacterial artificial chromosome (BAC) containing the fbxo47 mologous chromosomes of zygotene to pachytene oocytes, and allele with enhanced green fluorescent protein (EGFP) into foxl3 these signals disappeared in diplotene oocytes (Fig. 1 C–E). In mutants (SI Appendix, Fig. S6 and Table S3). None of the EGFP- −/− − − rec8a ovaries, although SYCP1 localized normally to the forming expressing germ cells in foxl3 / XX gonads (n = 5) exhibited SC axes of zygotene chromosomes, the signal became punctate at a spermatogenic progression (Fig. 2 H and I). Collectively, these pachytenelike stage (Fig. 1 F–H). These results suggest that SC axes −/− data strongly suggest that fbxo47 is a downstream factor of foxl3 prematurely disassembled in the rec8a oocytes and that rec8a is that is essential for suppressing spermatogenesis. required for the stability of the SC axis during the pachytene stage. To explore the possibility that abnormal oocytes were eliminated Two Pathways Downstream of foxl3 Contribute to Germline by apoptosis, we immunostained for activated caspase-3 (cleaved Feminization. As described above, two foxl3-downstream genes −/− caspase-3 [CC-3]) in wild-type and rec8a ovaries. We first mea- rec8a and fbxo47 are female-specific regulators of meiosis pro-
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