help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Molecular Endocrinology, doi:10.1210/me.2003-0393
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
18/3/653    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mazerbourg, S.
Right arrow Articles by Hsueh, A. J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mazerbourg, S.
Right arrow Articles by Hsueh, A. J. W.
Molecular Endocrinology 18 (3): 653-665
Copyright © 2004 by The Endocrine Society

Growth Differentiation Factor-9 Signaling Is Mediated by the Type I Receptor, Activin Receptor-Like Kinase 5

Sabine Mazerbourg, Cynthia Klein, Jaesook Roh, Noora Kaivo-Oja, David G. Mottershead, Olexander Korchynskyi, Olli Ritvos and Aaron J. W. Hsueh

Division of Reproductive Biology (S.M., C.K., J.R., A.J.W.H.), Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317; Developmental and Reproductive Biology Program (N.K.-O., D.G.M., O.R.), Biomedicum Helsinki and Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland; and Department of Cellular Biochemistry (O.K.), Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Aaron J. W. Hsueh, Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317. E-mail: aaron.hsueh{at}stanford.edu.

Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the TGF-ß superfamily that includes TGF-ß, activin, and bone morphogenetic proteins (BMPs). GDF-9 is indispensable for the development of ovarian follicles from the primary stage, and treatment with GDF-9 enhances the progression of early follicles into small preantral follicles. Similar to other TGF-ß family ligands, GDF-9 likely initiates signaling mediated by type I and type II receptors with serine/threonine kinase activity, followed by the phosphorylation of intracellular transcription factors named Smads. We have shown previously that GDF-9 interacts with the BMP type II receptor (BMPRII) in granulosa cells, but the type I receptor involved is unknown. Using P19 cells, we now report that GDF-9 treatment stimulated the CAGA-luciferase reporter known to be responsive to TGF-ß mediated by the type I receptor, activin receptor-like kinase (ALK)5. In contrast, GDF-9 did not stimulate BMP-responsive reporters. In addition, treatment with GDF-9 induced the phosphorylation of Smad2 and Smad3 in P19 cells, and the stimulatory effect of GDF-9 on the CAGA-luciferase reporter was blocked by the inhibitory Smad7, but not Smad6. We further reconstructed the GDF-9 signaling pathway using Cos7 cells that are not responsive to GDF-9. After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay. The roles of ALK5 and downstream pathway genes in mediating GDF-9 actions were further tested in ovarian cells. In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3. Furthermore, transfection with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 actions. In conclusion, although GDF-9 binds to the BMP-activated type II receptor, its downstream actions are mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins. Because ALK5 is a known receptor for TGF-ß, diverse members of the TGF-ß family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways.




This article has been cited by other articles:


Home page
 Biol. Reprod.Home page
C. J. McIntosh, S. Lun, S. Lawrence, A. H. Western, K. P. McNatty, and J. L. Juengel
The Proregion of Mouse BMP15 Regulates the Cooperative Interactions of BMP15 and GDF9
Biol Reprod, November 1, 2008; 79(5): 889 - 896.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. J. Edwards, K. L. Reader, S. Lun, A. Western, S. Lawrence, K. P. McNatty, and J. L. Juengel
The Cooperative Effect of Growth and Differentiation Factor-9 and Bone Morphogenetic Protein (BMP)-15 on Granulosa Cell Function Is Modulated Primarily through BMP Receptor II
Endocrinology, March 1, 2008; 149(3): 1026 - 1030.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
R. B. Gilchrist, M. Lane, and J. G. Thompson
Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality
Hum. Reprod. Update, March 1, 2008; 14(2): 159 - 177.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
H. E. McMahon, S. Sharma, and S. Shimasaki
Phosphorylation of Bone Morphogenetic Protein-15 and Growth and Differentiation Factor-9 Plays a Critical Role in Determining Agonistic or Antagonistic Functions
Endocrinology, February 1, 2008; 149(2): 812 - 817.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
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]

Home page
 Hum ReprodHome page
C. X. Yeo, R. B. Gilchrist, J. G. Thompson, and M. Lane
Exogenous growth differentiation factor 9 in oocyte maturation media enhances subsequent embryo development and fetal viability in mice
Hum. Reprod., January 1, 2008; 23(1): 67 - 73.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
E. S Feary, J. L Juengel, P. Smith, M. C French, A. R O'Connell, S. B Lawrence, S. M Galloway, G. H Davis, and K. P McNatty
Patterns of Expression of Messenger RNAs Encoding GDF9, BMP15, TGFBR1, BMPR1B, and BMPR2 During Follicular Development and Characterization of Ovarian Follicular Populations in Ewes Carrying the Woodlands FecX2W Mutation
Biol Reprod, December 1, 2007; 77(6): 990 - 998.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. G. Farnworth, Y. Wang, R. Escalona, P. Leembruggen, G. T. Ooi, and J. K. Findlay
Transforming Growth Factor-{beta} Blocks Inhibin Binding to Different Target Cell Types in a Context-Dependent Manner through Dual Mechanisms Involving Betaglycan
Endocrinology, November 1, 2007; 148(11): 5355 - 5368.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
I. Ben-Shlomo, R. Rauch, O. Avsian-Kretchmer, and A. J. W. Hsueh
Matching Receptome Genes with Their Ligands for Surveying Paracrine/Autocrine Signaling Systems
Mol. Endocrinol., August 1, 2007; 21(8): 2009 - 2014.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
D. L. Russell and R. L. Robker
Molecular mechanisms of ovulation: co-ordination through the cumulus complex
Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
L. Liu, S. Rajareddy, P. Reddy, C. Du, K. Jagarlamudi, Y. Shen, D. Gunnarsson, G. Selstam, K. Boman, and K. Liu
Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
Development, January 1, 2007; 134(1): 199 - 209.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
X. Gueripel, V. Brun, and A. Gougeon
Oocyte Bone Morphogenetic Protein 15, but not Growth Differentiation Factor 9, Is Increased During Gonadotropin-Induced Follicular Development in the Immature Mouse and Is Associated with Cumulus Oophorus Expansion
Biol Reprod, December 1, 2006; 75(6): 836 - 843.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Luo, A. H. Lin, E. Masliah, and T. Wyss-Coray
Bioluminescence imaging of Smad signaling in living mice shows correlation with excitotoxic neurodegeneration
PNAS, November 28, 2006; 103(48): 18326 - 18331.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. Orisaka, S. Orisaka, J.-Y. Jiang, J. Craig, Y. Wang, F. Kotsuji, and B. K. Tsang
Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage
Mol. Endocrinol., October 1, 2006; 20(10): 2456 - 2468.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
R. B. Gilchrist, L. J. Ritter, S. Myllymaa, N. Kaivo-Oja, R. A. Dragovic, T. E. Hickey, O. Ritvos, and D. G. Mottershead
Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation
J. Cell Sci., September 15, 2006; 119(18): 3811 - 3821.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
S. Mazerbourg and A. J.W. Hsueh
Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands
Hum. Reprod. Update, July 1, 2006; 12(4): 373 - 383.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
L J Spicer, P Y Aad, D Allen, S Mazerbourg, and A J Hsueh
Growth differentiation factor-9 has divergent effects on proliferation and steroidogenesis of bovine granulosa cells.
J. Endocrinol., May 1, 2006; 189(2): 329 - 339.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. Wang and S. K. Roy
Expression of Growth Differentiation Factor 9 in the Oocytes Is Essential for the Development of Primordial Follicles in the Hamster Ovary
Endocrinology, April 1, 2006; 147(4): 1725 - 1734.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
B. C Jayawardana, T. Shimizu, H. Nishimoto, E. Kaneko, M. Tetsuka, and A. Miyamoto
Hormonal regulation of expression of growth differentiation factor-9 receptor type I and II genes in the bovine ovarian follicle.
Reproduction, March 1, 2006; 131(3): 545 - 553.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
A. J. Levine and A. H. Brivanlou
GDF3, a BMP inhibitor, regulates cell fate in stem cells and early embryos
Development, January 15, 2006; 133(2): 209 - 216.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
A J W Hsueh, P Bouchard, and I Ben-Shlomo
Hormonology: a genomic perspective on hormonal research
J. Endocrinol., December 1, 2005; 187(3): 333 - 338.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
T. S. Hussein, D. A. Froiland, F. Amato, J. G. Thompson, and R. B. Gilchrist
Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins
J. Cell Sci., November 15, 2005; 118(22): 5257 - 5268.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
S. A. Pangas and M. M. Matzuk
The Art and Artifact of GDF9 Activity: Cumulus Expansion and the Cumulus Expansion-Enabling Factor
Biol Reprod, October 1, 2005; 73(4): 582 - 585.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Mazerbourg, K. Sangkuhl, C.-W. Luo, S. Sudo, C. Klein, and A. J. W. Hsueh
Identification of Receptors and Signaling Pathways for Orphan Bone Morphogenetic Protein/Growth Differentiation Factor Ligands Based on Genomic Analyses
J. Biol. Chem., September 16, 2005; 280(37): 32122 - 32132.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. H. Lin, J. Luo, L. H. Mondshein, P. ten Dijke, D. Vivien, C. H. Contag, and T. Wyss-Coray
Global Analysis of Smad2/3-Dependent TGF-{beta} Signaling in Living Mice Reveals Prominent Tissue-Specific Responses to Injury
J. Immunol., July 1, 2005; 175(1): 547 - 554.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
R. A. Dragovic, L. J. Ritter, S. J. Schulz, F. Amato, D. T. Armstrong, and R. B. Gilchrist
Role of Oocyte-Secreted Growth Differentiation Factor 9 in the Regulation of Mouse Cumulus Expansion
Endocrinology, June 1, 2005; 146(6): 2798 - 2806.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
J.L. Juengel and K.P. McNatty
The role of proteins of the transforming growth factor-{beta} superfamily in the intraovarian regulation of follicular development
Hum. Reprod. Update, March 1, 2005; 11(2): 144 - 161.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
N. Kaivo-Oja, D. G. Mottershead, S. Mazerbourg, S. Myllymaa, S. Duprat, R. B. Gilchrist, N. P. Groome, A. J. Hsueh, and O. Ritvos
Adenoviral Gene Transfer Allows Smad-Responsive Gene Promoter Analyses and Delineation of Type I Receptor Usage of Transforming Growth Factor-{beta} Family Ligands in Cultured Human Granulosa Luteal Cells
J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 271 - 278.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
J. E. I. Gittens, K. J. Barr, B. C. Vanderhyden, and G. M. Kidder
Interplay between paracrine signaling and gap junctional communication in ovarian follicles
J. Cell Sci., January 1, 2005; 118(1): 113 - 122.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
K P McNatty, L G Moore, N L Hudson, L D Quirke, S B Lawrence, K Reader, J P Hanrahan, P Smith, N P Groome, M Laitinen, et al.
The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology
Reproduction, October 1, 2004; 128(4): 379 - 386.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
R.B. Gilchrist, L.J. Ritter, M. Cranfield, L.A. Jeffery, F. Amato, S.J. Scott, S. Myllymaa, N. Kaivo-Oja, H. Lankinen, D.G. Mottershead, et al.
Immunoneutralization of Growth Differentiation Factor 9 Reveals It Partially Accounts for Mouse Oocyte Mitogenic Activity
Biol Reprod, September 1, 2004; 71(3): 732 - 739.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2004 by The Endocrine Society