In mammals, male fate is under the control of the master transcriptional regulator, SOX9: in its presence, somatic precursor cells of the embryonic gonads differentiate into Sertoli cells, the central organizers of testicular differentiation. Therefore, analyzing target genes of this transcription factor allows the elucidation of cellular commitment mechanisms at the genome level. ChIP-seq in murine and bovine wild-type testes combined with RNAseq from mouse testes lacking SOX9 was undertaken1. 142 sex-specific RNA splicing events were detected in the XY knockout testes, similar to XX ovaries. Surprisingly, nearly half these genes were were bound by SOX9 in wild type testes. This suggests that SOX9 mediates both transcription and differential splicing of its target genes, as seen in chondrogenesis2. FGFR2 has two splice isoforms and the 2c form is essential during but not after sex determination3. Validation of RNAseq/Chipseq data in a human Sertoli cell line indicated that SOX9 mediates differential RNA splicing of the FGFR2 gene through DNA binding. Our results suggests that RNA splicing of FGFR2 could be a fine-tuning mechanism to reduce FGF9 ligand binding function once sex has been determined and that RNA splicing could be important in sex determination in mammals, as in Drosophila.
1Lavery et al., NAR 2017
2Hata et al., JCI 2011
3Bagheri-Fam et al., Endocrinology 2017