TY - JOUR
T1 - Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice
AU - Pangas, Stephanie A.
AU - Li, Xiaohui
AU - Umans, Lieve
AU - Zwijsen, An
AU - Huylebroeck, Danny
AU - Gutierrez, Carolina
AU - Wang, Degang
AU - Martin, James F.
AU - Jamin, Soazik P.
AU - Behringer, Richard R.
AU - Robertson, Elizabeth J.
AU - Matzuk, Martin M.
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=37549046846&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37549046846&partnerID=8YFLogxK
U2 - 10.1128/MCB.01404-07
DO - 10.1128/MCB.01404-07
M3 - Article
C2 - 17967875
AN - SCOPUS:37549046846
SN - 0270-7306
VL - 28
SP - 248
EP - 257
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 1
ER -