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Molecular and Cellular Biology, January 2008, p. 248-257, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01404-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice{triangledown} ,{dagger}

Stephanie A. Pangas,1* Xiaohui Li,1 Lieve Umans,2 An Zwijsen,2 Danny Huylebroeck,2 Carolina Gutierrez,1 Degang Wang,3 James F. Martin,3 Soazik P. Jamin,4 Richard R. Behringer,4 Elizabeth J. Robertson,5 and Martin M. Matzuk1,6,7*

Departments of Pathology,1 Molecular and Cellular Biology,6 Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,7 Department of Developmental Biology (VIB7), Flanders Interuniversity Institute for Biotechnology (VIB), and Laboratory of Molecular Biology (CELGEN), Division of Molecular and Developmental Genetics, Department of Human Genetics (DME), Leuven-VIB, Belgium,2 Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030,3 Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,4 Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom5

Received 4 August 2007/ Returned for modification 21 September 2007/ Accepted 19 October 2007

The transforming growth factor β (TGFβ) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGFβ function and SMAD2 or SMAD4 mutations. There are limited mouse models for the BMP signaling SMADs (BR-SMADs) 1, 5, and 8 because of embryonic lethality and suspected genetic redundancy. Using tissue-specific ablation in mice, we deleted the BR-SMADs from somatic cells of ovaries and testes. Single conditional knockouts for Smad1 or Smad5 or mice homozygous null for Smad8 are viable and fertile. Female double Smad1 Smad5 and triple Smad1 Smad5 Smad8 conditional knockout mice become infertile and develop metastatic granulosa cell tumors. Male double Smad1 Smad5 conditional knockout mice are fertile but demonstrate metastatic testicular tumor development. Microarray analysis indicated significant alterations in expression of genes related to the TGFβ pathway, as well as genes involved in infertility and extracellular matrix production. These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation.

* Corresponding author. Mailing address: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-5898. Fax: (713) 798-5833. E-mail for Stephanie A. Pangas: spangas{at}bcm.edu. E-mail for Martin M. Matzuk: mmatzuk{at}bcm.edu

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2008, p. 248-257, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01404-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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