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Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues.

ABSTRACT: Biochemical studies have shown that Smad7 blocks signal transduction of transforming growth factor beta (TGFbeta); however, its in vivo functions are largely unknown. To determine the functions of Smad7, we have expressed Smad7 in transgenic mice, utilizing a keratin K5 promoter (K5.Smad7). K5.Smad7 mice exhibited pathological changes in multiple tissues and died within 10 days after birth. These mice were born with open eyelids and corneal defects, significantly delayed and aberrant hair follicle morphogenesis, and hyperproliferation in the epidermis and other stratified epithelia. Furthermore, K5.Smad7 mice developed severe thymic atrophy and massive thymocyte death, suggesting that Smad signaling in thymic epithelia is essential for thymocyte survival. Interestingly, in addition to a reduction in Smad phosphorylation, the protein levels of the receptors for TGFbeta, activin and bone morphogenetic protein were significantly decreased in the affected tissues of K5.Smad7 mice. Our study provides evidence that Smad7 is a potent in vivo inhibitor for signal transduction of the TGFbeta superfamily during development and maintenance of homeostasis of multiple epithelial tissues.

SUBMITTER: He W

PROVIDER: S-EPMC126032 | biostudies-literature | 2002 Jun

REPOSITORIES: biostudies-literature

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Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues.

He Wei W Li Allen G AG Wang Dongyan D Han Shuhua S Zheng Biao B Goumans Marie-José MJ Ten Dijke Peter P Wang Xiao-Jing XJ

The EMBO journal 20020601 11

Biochemical studies have shown that Smad7 blocks signal transduction of transforming growth factor beta (TGFbeta); however, its in vivo functions are largely unknown. To determine the functions of Smad7, we have expressed Smad7 in transgenic mice, utilizing a keratin K5 promoter (K5.Smad7). K5.Smad7 mice exhibited pathological changes in multiple tissues and died within 10 days after birth. These mice were born with open eyelids and corneal defects, significantly delayed and aberrant hair follic ...[more]

PMID: 12032071

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Project description:Tooth morphogenesis involves dynamic changes in shape and size as it proceeds through the bud, cap, and bell stages. This process requires exact regulation of cell proliferation and differentiation. Smad7, a general antagonist against transforming growth factor-? (TGF-?) signaling, is necessary for maintaining homeostasis and proper functionality in many organs. While TGF-? signaling is widely involved in tooth morphogenesis, the precise role of Smad7 in tooth development remains unknown. In this study, we showed that Smad7 is expressed in the developing mouse molars with a high level in the dental epithelium but a moderate to weak level in the dental mesenchyme. Smad7 deficiency led to a profound decrease in tooth size primarily due to a severely compromised cell proliferation capability in the dental epithelium. Consistent with the tooth shrinkage phenotype, RNA sequencing (RNA-seq) analysis revealed that Smad7 ablation downregulated genes referred to epithelial cell proliferation and cell cycle G1/S phase transition, whereas the upregulated genes were involved in responding to TGF-? signaling and cell cycle arrest. Among these genes, the expression of Cdkn1a (encoding p21), a negative cell proliferation regulator, was remarkably elevated in parallel with the diminution of Ccnd1 encoding the crucial cell cycle regulator cyclin D1 in the dental epithelium. Meanwhile, the expression level of p-Smad2/3 was ectopically elevated in the developing tooth germ of Smad7 null mice, indicating the hyperactivation of the canonical TGF-? signaling. These effects were reversed by addition of TGF-? signaling inhibitor in cell cultures of Smad7-/- molar tooth germs, with rescued expression of cyclin D1 and cell proliferation rate. In sum, our studies demonstrate that Smad7 functions primarily as a positive regulator of cell proliferation via inhibition of the canonical TGF-? signaling during dental epithelium development and highlight a crucial role for Smad7 in regulating tooth size.

Project description:Heart failure (HF) is a functional lack of myocardial performance due to a loss of molecular control over increases in calcium and ROS, resulting in proteolytic degradative advances and cardiac remodeling. Mitochondria are the molecular powerhouse of cells, shifting the sphere of cardiomyocyte stability and performance. Functional mitochondria rely on the molecular abilities of safety factors such as TFAM to maintain physiological parameters. Mitochondrial transcription factor A (TFAM) creates a mitochondrial nucleoid structure around mtDNA, protecting it from mutation, inhibiting NFAT (ROS activator/hypertrophic stimulator), and transcriptionally activates Serca2a to decrease calcium mishandling. Calpain1 and MMP9 are proteolytic degratory factors that play a major role in cardiomyocyte decline in HF. Current literature depicts major decreases in TFAM as HF progresses. We aim to assess TFAM function against Calpain1 and MMP9 proteolytic activity and its role in cardiac remodeling. To this date, no publication has surfaced describing the effects of aortic banding (AB) as a surgical HF model in TFAM-TG mice. HF models were created via AB in TFAM transgenic (TFAM-TG) and C57BLJ-6 (WT) mice. Eight weeks post AB, functional analysis revealed a successful banding procedure, resulting in cardiac hypertrophy as observed via echocardiography. Pulse wave and color doppler show increased aortic flow rates as well as turbulent flow at the banding site. Preliminary results of cardiac tissue immuno-histochemistry of HF-control mice show decreased TFAM and compensatory increases in Serca2a fluorescent expression, along with increased Calpain1 and MMP9 expression. Protein, RNA, and IHC analysis will further assess TFAM-TG results post-banding. Echocardiography shows more cardiac stability and functionality in HF-induced TFAM-TG mice than the control counterpart. These findings complement our published in vitro results. Overall, this suggests that TFAM has molecular therapeutic potential to reduce protease expression.

Dataset Information

Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues.

Publications

Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues.

Similar Datasets

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