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Human Reproduction Update Advance Access originally published online on April 7, 2006
Human Reproduction Update 2006 12(4):373-383; doi:10.1093/humupd/dml014
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands

Sabine Mazerbourg2 and Aaron J.W. Hsueh1

Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA

1 To whom correspondence should be addressed at: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Dr., Room A344, Stanford, CA 94305-5317, USA. E-mail: aaron.hsueh{at}stanford.edu

2 Present address: Université Henri Poincaré—Nancy 1, Faculté des Sciences, Boulevard des aiguillettes, UPRES EA 3442: Aspects cellulaires et moléculaires de la reproduction et du développement, BP239, 54506 Vandoeuvre les Nancy cedex, France

Submitted on December 5, 2005; resubmitted on January 30, 2006; accepted on March 7, 2006

Recent advances in genomic sequencing allow a new paradigm in hormonal research, and a comparative genomic approach facilitates the identification of receptors and signalling mechanisms for orphan ligands of the transforming growth factor ß (TGFß) superfamily. Instead of purifying growth differentiation factor 9 (GDF9) receptor proteins for identification, we hypothesized that GDF9, like other ligands in the TGFß family, activates type II and type I serine/threonine kinase receptors. Because searches of the human genome for genes with sequence homology to known serine/threonine kinase receptors failed to reveal uncharacterized receptor genes, GDF9 likely interacts with the known type II and type I activin receptor-like kinase (ALK) receptors in granulosa cells. We found that co-treatment with the bone morphogenetic protein (BMP) type II receptor (BMPRII) ectodomain blocks GDF9 activity. Likewise, in a GDF9-non-responsive cell line, overexpression of ALK5, but none of the other six type I receptors, conferred GDF9 responsiveness. The roles of BMPRII and ALK5 as receptors for GDF9 were validated in granulosa cells using gene ‘knock-down’ approaches. Furthermore, we demonstrated the roles of BMPRII, ALK3 and ALK6 as the receptors for the orphan ligands GDF6, GDF7 and BMP10. Thus, evolutionary tracing of polypeptide ligands, receptors and downstream signalling molecules in their respective ‘subgenomes’ facilitates a new approach for hormonal research.

Key words: BMP / GDF9 / granulosa cell / ovary / TGFß receptors


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L. J Spicer, P. Y Aad, D. T Allen, S. Mazerbourg, A. H Payne, and A. J Hsueh
Growth Differentiation Factor 9 (GDF9) Stimulates Proliferation and Inhibits Steroidogenesis by Bovine Theca Cells: Influence of Follicle Size on Responses to GDF9
Biol Reprod, February 1, 2008; 78(2): 243 - 253.
[Abstract] [Full Text] [PDF]


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