Smad7是调控TGF－beta信号通路的一个关键蛋白，TGF－beta具有了多种生物学功能，包括细胞分化、肿瘤生长、免疫调节、组织纤维化、以及胚胎早期发育等多个环节。Smad7特异性结合TGF－beta受体，抑制TGF－beta信号通路的转导，在多种人类疾病中都有Smad7的表达异常，但Smad7的活体生物学功能一直不太清楚。

在该工作中，陈雁研究组与美国Indiana大学的Shou教授研究组合作，首次建立一个条件性Smad7基因敲除小鼠模型。发现Smad7功能缺失可以在小鼠胚胎中导致先天性心脏病，小鼠心脏出现室间隔缺损、主动脉和肺动脉移位、心肌形态异常。在少数存活的Smad7基因敲除成年小鼠中，出现心脏功能紊乱、心律不齐。在进一步的研究中，发现胚胎期心脏的TGF－beta信号通路、细胞增殖、以及细胞凋亡都发生了相应的变化。这一研究成果第一次揭示了Smad7与先天性心脏病的关系，提示Smad7与动物心脏发育和心脏功能密切相关。该项目受到了国家重大科学计划等基金的支持。

推荐原始出处：

J. Biol. Chem., Vol. 284, Issue 1, 292-300, January 2, 2009

Smad7 Is Required for the Development and Function of the Heart*

Qian Chen, Hanying Chen, Dawei Zheng, Chenzhong Kuang, Hong Fang||, Bingyu Zou, Wuqiang Zhu, Guixue Bu, Ting Jin, Zhenzhen Wang, Xin Zhang, Ju Chen**, Loren J. Field, Michael Rubart, Weinian Shou||1, and Yan Chen2

From the  Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and ||Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the ?Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the **Department of Medicine, University of California San Diego, La Jolla, California 92093

Transforming growth factor-β (TGF-β) family members, including TGF-βs, activins, and bone morphogenetic proteins, exert diverse biological activities in cell proliferation, differentiation, apoptosis, embryonic development, and many other processes. These effects are largely mediated by Smad proteins. Smad7 is a negative regulator for the signaling of TGF-β family members. Dysregulation of Smad7 is associated with pathogenesis of a variety of human diseases. However, the in vivo physiological roles of Smad7 have not been elucidated due to the lack of a mouse model with significant loss of Smad7 function. Here we report generation and initial characterization of Smad7 mutant mice with targeted deletion of the indispensable MH2 domain. The majority of Smad7 mutant mice died in utero due to multiple defects in cardiovascular development, including ventricular septal defect and non-compaction, as well as outflow tract malformation. The surviving adult Smad7 mutant mice had impaired cardiac functions and severe arrhythmia. Further analyses suggest that Smad2/3 phosphorylation was elevated in atrioventricular cushion in the heart of Smad7 mutant mice, accompanied by increased apoptosis in this region. Taken together, these observations pinpoint an important role of Smad7 in the development and function of the mouse heart in vivo.