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

Miles, Denise C., Wakeling, Stephanie I., Stringer, Jessica M., van den Bergen, Jocelyn A., Wilhelm, Dagmar, Sinclair, Andrew H. and Western, Patrick S. (2013) Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development. PloS One, 8 1: . doi:10.1371/journal.pone.0054606

Author Miles, Denise C.
Wakeling, Stephanie I.
Stringer, Jessica M.
van den Bergen, Jocelyn A.
Wilhelm, Dagmar
Sinclair, Andrew H.
Western, Patrick S.
Title Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-01-16
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pone.0054606
Open Access Status DOI
Volume 8
Issue 1
Total pages 16
Place of publication San Francisco, United States
Publisher Public Library of Science
Language eng
Formatted 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 Tgfß family members has indicated that Tgfß’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, TGFß’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 TGFb signaling is required for testis cord formation during the critical testisdetermining 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/TGFß receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFß and Activin signaling during testis formation and male germ cell development.
Keyword Female sex-reversal
Meiotic initiation
Retinoic acid
Ovarian development
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes Article # e54606

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
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