Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development

Denise Catherine Miles, Stephanie Wakeling, Jessica Stringer, Jocelyn A van den Bergen, Dagmar Wilhelm, Andrew H Sinclair, Patrick Stephen Western

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58 Citations (Scopus)

Abstract

The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfbeta family members has indicated that Tgfbeta s are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin s, TGFbeta s, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFbeta signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFbeta receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFbeta and Activin signaling during testis formation and male germ cell development.
Original languageEnglish
Article numbere54606
Number of pages16
JournalPLoS ONE
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

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