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Molecular and Cellular Biology, December 2008, p. 7001-7011, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00732-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Redundant Roles of SMAD2 and SMAD3 in Ovarian Granulosa Cells In Vivo {triangledown}

Qinglei Li,1 Stephanie A. Pangas,1 Carolina J. Jorgez,1 Jonathan M. Graff,4 Michael Weinstein,5 and Martin M. Matzuk1,2,3*

Departments of Pathology,1 Molecular and Cellular Biology,2 Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,3 Center for Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390,4 Department of Molecular Genetics and Division of Human Cancer Genetics, Ohio State University, 484 W. 12th Ave., Columbus, Ohio 432105

Received 7 May 2008/ Returned for modification 23 July 2008/ Accepted 13 September 2008

Transforming growth factor β (TGF-β) superfamily members are critical in maintaining cell growth and differentiation in the ovary. Although signaling of activins, TGF-βs, growth differentiation factor 9, and nodal converge preferentially to SMAD2 and SMAD3, the in vivo functions and redundancy of these SMADs in the ovary and female reproduction remain largely unidentified. To circumvent the deleterious phenotypic aspects of ubiquitous deletion of Smad2 and Smad3, a conditional knockout strategy was formulated to selectively inactivate Smad2, Smad3, or both Smad2 and Smad3 in ovarian granulosa cells. While granulosa cell ablation of individual Smad2 or Smad3 caused insignificant changes in female fertility, deletion of both Smad2 and Smad3 led to dramatically reduced female fertility and fecundity. These defects were associated with the disruption of multiple ovarian processes, including follicular development, ovulation, and cumulus cell expansion. Furthermore, the impaired expansion of cumulus cells may be partially associated with altered cumulus expansion-related transcripts that are regulated by SMAD2/3 signaling. Our results indicate that SMAD2 and SMAD3 function redundantly in vivo to maintain normal female fertility and further support the involvement of an intraovarian SMAD2/3 pathway in mediating oocyte-produced signals essential for coordinating key events of the ovulatory process.

* Corresponding author. Mailing address: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6451. Fax: (713) 798-5833. E-mail: mmatzuk{at}bcm.tmc.edu

{triangledown} Published ahead of print on 22 September 2008.

Molecular and Cellular Biology, December 2008, p. 7001-7011, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00732-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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