Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The transforming growth factor beta (TGFbeta) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGFbeta 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 TGFbeta 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.

Original publication

DOI

10.1128/MCB.01404-07

Type

Journal article

Journal

Mol Cell Biol

Publication Date

01/2008

Volume

28

Pages

248 - 257

Keywords

Animals, Cell Transformation, Neoplastic, Cells, Cultured, Female, Fertility, Gene Deletion, Gene Expression Regulation, Neoplastic, Granulosa Cell Tumor, Male, Mice, Mice, Knockout, Mutation, Neoplasm Metastasis, Ovary, Sertoli Cell Tumor, Smad1 Protein, Smad5 Protein, Smad8 Protein, Testicular Neoplasms, Testis