Conditional knockout of the <i>Smad1</i> gene

Huang, Shixia; Tang, Binwu; Usoskin, Dmitry; Lechleider, Robert J.; Jamin, Soazik P.; Li, Cuiling; Anzano, Mario A.; Ebendal, Ted; Deng, Chu‐Xia; Roberts, Anita B.

doi:10.1002/gene.10059

Cited by 47 publications

(35 citation statements)

References 14 publications

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“…Smad8 null mice are viable and fertile (1), while Smad1 and Smad5 homozygous and heterozygous null embryos die at midgestation (8,53). Several conditional alleles of Smad1 and Smad5 have been generated to circumvent the lethality and allow for the analysis of BR-SMADs in later-stage embryonic and adult tissues (1,21,54). However, few adult tissue-specific knockout mice have yet to be reported.…”

Section: Discussionmentioning

confidence: 99%

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

Pangas¹,

Li²,

Umans³

et al. 2008

Molecular and Cellular Biology

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

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Section: Discussionmentioning

confidence: 99%

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

Pangas¹,

Li²,

Umans³

et al. 2008

Molecular and Cellular Biology

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204

224

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“…We further investigated whether the reduction of Smad1 expression improves diabetic glomerular changes by using heterozygous SMAD1 knockout (KO) mice, which were provided from Anita B. Roberts (National Cancer Institute, Bethesda, MD) (34). After the induction of diabetes, body weights, blood pressure, and HbA 1c in diabetic SMAD1 heterozygous KO mice did not differ from diabetic WT mice (Supplementary Table 4).…”

Section: Heterozygous Smad1 Knockout Mice Exhibit Attenuated Mesangiamentioning

confidence: 99%

Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy

et al. 2015

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Diabetic nephropathy is the leading cause of end-stage renal disease. It is pathologically characterized by the accumulation of extracellular matrix in the mesangium, of which the main component is a1/a2 type IV collagen (Col4a1/a2). Recently, we identified Smad1 as a direct regulator of Col4a1/a2 under diabetic conditions in vitro. Here, we demonstrate that Smad1 plays a key role in diabetic nephropathy through bone morphogenetic protein 4 (BMP4) in vivo. Smad1-overexpressing mice (Smad1-Tg) were established, and diabetes was induced by streptozotocin. Nondiabetic Smad1-Tg did not exhibit histological changes in the kidney; however, the induction of diabetes resulted in an ∼1.5-fold greater mesangial expansion, consistent with an increase in glomerular phosphorylated Smad1. To address regulatory factors of Smad1, we determined that BMP4 and its receptor are increased in diabetic glomeruli and that diabetic Smad1-Tg and wild-type mice treated with a BMP4-neutralizing antibody exhibit decreased Smad1 phosphorylation and ∼40% less mesangial expansion than those treated with control IgG. Furthermore, heterozygous Smad1 knockout mice exhibit attenuated mesangial expansion in the diabetic condition. The data indicate that BMP4/Smad1 signaling is a critical cascade for the progression of mesangial expansion and that blocking this signal could be a novel therapeutic strategy for diabetic nephropathy.Diabetic nephropathy is a life-threatening complication of diabetes and the leading cause of end-stage renal disease (1). The structural features of diabetic nephropathy include thickening of the glomerular basement membrane (GBM) and mesangial matrix expansion (2,3). Mesangial matrix expansion is pathologically important because it leads to glomerulosclerosis accompanied by various tubulointerstitial damages and subsequent nephron loss (4,5). In addition, the severity of mesangial matrix expansion is clinically important because it is closely associated with the decline of the glomerular filtration rate (6).Mesangial matrix expansion is characterized by increased amounts of extracellular matrix (7), particularly a1/a2 type IV collagen (Col4a1/a2) (8). Although various peptides or growth factors are shown to mediate the regulation of this key component, the protein responsible for its direct regulation remains to be determined.Because various injuries of epithelial, endothelial, and mesangial cells converge on the accumulation of Col4a1/a2 in the mesangium, mesangial cells presumably play a central role for the regulation of Col4a1/a2, even if they are not the primary target of injury (9). Therefore, we attempted to elucidate the direct regulation of Col4a1/a2 under diabetic conditions and demonstrate that Smad1 can transcriptionally regulate Col4a1/a2 in the presence of advanced glycation end products in mesangial cells (10).Smad1 is an intracellular molecule originally cloned as a signal transducer of the transforming growth factor (TGF)-b superfamily (11). In response to these stimuli, Smad1 is phosphorylated at the COOH...

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“…Floxed Smad1 mice were generated in the laboratory of Dr Anita B. Roberts (Huang et al, 2002), in which the Smad1 gene locus was targeted by loxP-PGKneo-loxP-exon2-loxP. We then removed the PGKneo cassette by crossing the floxed Smad1 heterozygous mice with EIIa-Cre mice (Xu et al, 2001) to generate the Smad1 fx allele (loxP-exon2-loxP) in order to avoid non-specific genetic interference caused by PGKneo cassette insertion.…”

Section: Mouse Strains and Breedingmentioning

confidence: 99%

Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate fetal lung development

Chen

et al. 2011

Development

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SUMMARYBone morphogenetic protein 4 (Bmp4) is essential for lung development. To define the intracellular signaling mechanisms by which Bmp4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation and, consequently, severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor 1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 was associated with reduced Wif1 expression and increased Wnt/-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. This suggests a novel regulatory loop of Bmp4-Smad1-Wif1-Wnt/-catenin in coordinating BMP and Wnt pathways to control fetal lung development.

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Conditional knockout of the Smad1 gene

Cited by 47 publications

References 14 publications

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

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

Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy

Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate fetal lung development

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