The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Investigating activin A effects on fetal male germ cell fate (#369)

Sarah C Moody 1 2 , Patrick Western 1 , Kate L Loveland 1 2
  1. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Sciences, School of Clinical Sciences, Monash University, Clayton, VIC, Australia

Germline development in the fetal testis underpins adult male fertility, and its disruption is considered permissive for testicular germ cell tumour emergence in young men.  Signalling by TGFβ superfamily members, including activin A, affects germ cell proliferation and differentiation.  Fetuses may be exposed to elevated activin A during pre-eclampsia, maternal infections and from maternal medications and the effects on male fertility are unknown. This study uses the human TCam-2 seminoma cell line, which is characteristic of fetal male germ cells, termed gonocytes, as well as mouse and human gonads to identify activin actions on the fetal male germline. TCam-2 cells were cultured with activin A (1.25 to 50 ng/mL) for 48 hours (n=3), or for 6, 24 and 48 hours with 5 ng/mL (n=5) in serum-free conditions, and transcripts were measured by qRT-PCR.  Because TCam-2 cells produce an activin inhibitor, TDGF1 (the Nodal co-receptor), TDGF1 was reduced using siRNA prior to activin exposure (24 hours, n=2).  Downstream targets were significantly upregulated (KIT, NODAL; gonocytes proliferation markers) and downregulated (DNMT3L, NANOS2; differentiation markers).  This was similar in both the normal and knockdown conditions, indicating these genes are direct activin targets and that activin promotes a less differentiated state in TCam-2 cells.  TGFβ1 and TGFβ2 exposure had minimal effect.  Preliminary data from human first trimester cultured gonads indicates KIT is downregulated by activin A (5 ng/mL, 72 hours), consistent with previous outcomes using cultured human testis cancer (seminoma) fragments (1). Additionally, embryonic day 13.5 mouse testes cultured in serum-containing media with 10 µM SB431542 (activin/nodal/TGFβ inhibitor) or vehicle control for 48 hours (n=5) resulted in significantly higher Kit and significantly lower Dnmt3l levels.  These approaches demonstrate that the somatic cell environment regulates gonocyte responsiveness to activin A, and highlight the importance of this ligand on their development.

  1. 1. Jorgensen et al 2014. Hanging drop cultures of human testis and testis cancer samples: a model used to investigate activin treatment effects in a preserved niche. Br J Cancer, 110, 2604-14.