foxl3 , a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka

Abstract

Germ cells have the ability to differentiate into eggs and sperm and must determine their sexual fate. In vertebrates, the mechanism of commitment to oogenesis following the sexual fate decision in germ cells remains unknown.Forkhead-box protein L3(foxl3) is a switch gene involved in the germline sexual fate decision in the teleost fish medaka (Oryzias latipes). Here, we show thatfoxl3organizes two independent pathways of oogenesis regulated byREC8 meiotic recombination protein a(rec8a), a cohesin component, andF-box protein(FBP) 47(fbxo47), a subunit of E3 ubiquitin ligase. In mutants of either gene, germ cells failed to undergo oogenesis but developed normally into sperm in testes. Disruption ofrec8aresulted in arrest at a meiotic pachytenelike stage specifically in females, revealing a sexual difference in meiotic progression. Analyses offbxo47mutants showed that this gene regulates transcription factors that facilitate folliculogenesis:LIM homeobox 8(lhx8b),factor in the germlineα (figla), andnewborn ovary homeobox(nobox). Interestingly, we found that thefbxo47pathway ensures that germ cells do not deviate from an oogenic pathway until they reach diplotene stage. The mutant phenotypes together with the timing of their expression imply that germline feminization is established during early meiotic prophase I.

Germline sexual fate is determined by the antagonistic action of dmrt1 and foxl3/foxl2 in tilapia

“…Disruption of foxl3 in medaka, which is specifically expressed in germ cells, initiates spermatogenesis in a female gonadal environment, thus identifying a new mechanism for germline sexual fate decision in vertebrates (Nishimura et al, 2015). Further study has shown that foxl3 initiates oogenesis by directly regulating rec8a and fbxo47 in medaka (Kikuchi et al, 2019(Kikuchi et al, , 2020. However, it is unclear whether foxl3 is a conserved factor for germline sexual fate decision in other fish species.…”

Functional Modules in Gametogenesis

“…Recent studies have revealed two genes, rec8a ( REC8 meiotic recombination protein a ) and fbxo47 ( F-box protein 47 ) to be direct targets of Foxl3. Similar to foxl3 , rec8a and fbxo47 are expressed in female type II germ cells, and loss-of-function mutations cause female-specific sterility and ovarian dysgenesis, suggesting their crucial roles in oogenesis ( Kikuchi et al, 2019 ; Kikuchi et al, 2020 ).…”

“…Similarly, medaka rec8a –/– fish display defects in synapsis between homologous chromosomes during meiotic prophase I, which results in meiotic arrest at the pachytene-like stage. The phenotypes of medaka rec8a –/– are female specific: medaka rec8a –/– males are fertile and develop normal testes containing mature sperm ( Kikuchi et al, 2020 ). It seems likely that the rec8a paralogous gene rec8b contributes to spermatogenesis.…”

FBXO47 is essential for preventing the synaptonemal complex from premature disassembly in mouse male meiosis

“…In the teleost fish medaka, fbxo47 mutant XX germ cells exhibit abnormally condensed chromosomes in ovaries and fail to undergo oogenesis after diplotene, showing that the sexual fate of XX germ cells turns into spermatogenesis (Kikuchi et al, 2020). Thus, fbxo47 is involved in the regulation of cell division in ovaires, and in turn the suppression of spermatogenesis in female germ cells in medaka.…”

“…In C. elegance, mutation in prom-1 that encodes putative Fbxo47 homolog, showed reduced homologous chromosome pairing and bivalent formation (Jantsch et al, 2007). In medaka fish, fbxo47 mutant fails to complete meiotic prophase in female but switches developmental fate from oogenesis into spermatogenesis (Kikuchi et al, 2020). In mouse, Fbxo47 gene that has previously been identified as a meiotic gene by single cell RNA-seq analysis of testes, is essential for mouse spermatogenesis (Chen et al, 2018) (Hua et al, 2019).…”