Overexpression of Smad2 reveals its concerted action with Smad4 in regulating TGF-β-mediated epidermal homeostasis
Overexpression of Smad2 reveals its concerted action with Smad4 in regulating TGF-β-mediated epidermal homeostasis
复制标题
DOI：
10.1006/dbio.2001.0332
复制
发表时间：
2001-08-01
影响因子：
2.7
通讯作者：
Chai, Y
中科院分区：
文献类型：
--
作者：
Ito, Y;Sarkar, P;Chai, Y
转化生长因子- β (tgf - β)超家族的成员是上皮生长的关键调节因子，可以改变角质形成细胞的分化。tgf - β信号转导依赖于配体特异性I型和II型受体的异质复合物对Smad蛋白的磷酸化和激活。为了了解tgf - β和激活素特异性Smad的功能，我们在角蛋白14启动子的控制下，在表皮中产生过表达Smad2的转基因小鼠。Smad2的过表达会增加内源性Smad4和tgf - β 1的表达，而Smad2的杂合缺失会降低它们的表达水平，这表明Smad2和-4在皮肤发育过程中协同调节tgf - β信号传导。这些转基因小鼠毛发生长迟缓，耳朵发育不全，尾巴较短。在他们的皮肤中，表皮严重增厚，表皮结构紊乱，基底膜难以区分，真皮纤维化。这些异常表型是由于基底表皮细胞增殖增加和角化细胞分化程序异常所致。外胚层来源的牙釉质结构也异常。总的来说，我们的研究首次提供了体内证据，通过提供tgf - β信号的自动反馈，Smad2在调节tgf - β介导的表皮稳态中起着关键作用。(C) 2001学术出版社。
Members of the transforming growth factor-beta (TGF-beta) superfamily are critical regulators for epithelial growth and can alter the differentiation of keratinocytes. Transduction of TGF-beta signaling depends on the phosphorylation and activation of Smad proteins by heteromeric complexes of ligand-specific type I and II receptors. To understand the function of TGF-beta and activin-specific Smad, we generated transgenic mice that overexpress Smad2 in epidermis under the control of keratin 14 promoter. Overexpression of Smad2 increases endogenous Smad4 and TGF-beta1 expression while heterozygous loss of Smad2 reduces their expression levels, suggesting a concerted action of Smad2 and -4 in regulating TGF-beta signaling during skin development. These transgenic mice have delayed hair growth, underdeveloped ears, and shorter tails. In their skin, there is severe thickening of the epidermis with disorganized epidermal architecture, indistinguishable basement membrane, and dermal fibrosis. These abnormal phenotypes are due to increased proliferation of the basal epidermal cells and abnormalities in the program of keratinocyte differentiation. The ectodermally derived enamel structure is also abnormal. Collectively, our study presents the first in vivo evidence that, by providing an auto-feedback in TGF-beta signaling, Smad2 plays a pivotal role in regulating TGF-beta -mediated epidermal homeostasis. (C) 2001 Academic Press.