Oral Presentation ESA-SRB-APEG-NZSE 2022

MEK1/2 regulates male germline development in an FGF independent manner (#35)

Rheannon Blucher 1 2 , Rachel Lim 3 , Ellen Jarred 1 2 , Marnie Blewitt 3 , Matthew Ritchie 3 , Patrick Western 1 2
  1. Centre for Reproductive Health, Hudson Institute for Medical Research, Clayton, Vic, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, Vic, Australia
  3. Epigenetics and Development Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia

Male or female germline development depends on sex-specific somatic signalling in the developing testis or ovary. Disrupted testis and germline development is strongly associated with testis cancer in humans. In mice, Sry and Sox9 promote testis and male germline development by inducing genes, including Fgf9, that promote testis formation and inhibit ovarian development. FGF9 is required for testis development and has been implicated as a key determinant of male germline differentiation, however, the mechanisms through which it signals are unknown. As FGFs signal through Mitogen-Activated Protein Kinase (MAPK) in other tissues, we explored whether FGF9 regulates male germline development through MAPK using an ex vivo organ culture model. Embryonic day (E)11.5-12.5 Oct4GFP transgenic mouse testes were cultured with FGF receptor or MEK1/2 inhibitors for 24, 72 or 96 hours, with impacts on germ cell development determined using flow cytometry, immunofluorescence and RNA sequencing. Inhibition of MEK1/2 blocked mitotic arrest and broadly disrupted the transcription of male germline markers and upregulation of key male germline proteins DPPA4 and DNMT3L. Surprisingly, despite FGF signalling inhibition from E12.5 for 72 hours, germ cells entered mitotic arrest normally and expressed the male specific transcriptional program, although mitotic arrest was mildly disrupted following inhibition from E11.5 for 96 hours. RNA sequencing in isolated germ cells identified 25 and 1403 genes that were not properly expressed after 24 and 72 hours of MEK1/2 inhibition, but only 43 genes and 1 gene after 24 and 72 hours of FGF receptor inhibition. Together, these data indicate essential roles for MEK1/2 signalling in male germline differentiation, but a surprisingly limited role for FGF signalling. Our data strongly indicate that additional ligands acting through MEK1/2 play a significant role in male germline differentiation and highlights a need for further understanding of the mechanisms underlying male germline development.