Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grants HD32067 (to M.M.M.), HD44156 (to E.J.R.), HD12324 (to J.F.M.), and HD30284 (to R.R.B.), a European Union grant (T-Angiovasc QLG1-CT-2001-01032) and Interuniversity Attraction Poles Programme-Belgian Science Policy project IUAP5/35 (to L.U., A.Z., and D.H.), and a Ruth L. Kirschstein NRSA fellowship (5F32HD46335) and Burroughs Wellcome Career Award in the Biomedical Sciences grant (to S.A.P.).

We thank Wylie Vale (Salk Institute, La Jolla, CA) for the gift of the inhibin α polyclonal antibody, Milton Finegold and Alan Herron (Baylor College of Medicine) for pathological assessment of male tumors, Mai Tran (Baylor College of Medicine) for technical assistance, Lori-Ann Mistretta for assistance with GSEA, and Herman Dierick and Aleksandar Rajkovic for discussions and critical reading of the manuscript.