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转化生长因子-β信号传导对于关节形态发生至关重要。

TGF-beta signaling is essential for joint morphogenesis.

作者信息

Spagnoli Anna, O'Rear Lynda, Chandler Ronald L, Granero-Molto Froilan, Mortlock Douglas P, Gorska Agnieszka E, Weis Jared A, Longobardi Lara, Chytil Anna, Shimer Kimberly, Moses Harold L

机构信息

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

出版信息

J Cell Biol. 2007 Jun 18;177(6):1105-17. doi: 10.1083/jcb.200611031.

DOI:10.1083/jcb.200611031
PMID:17576802
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2064369/
Abstract

Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor beta (TGF-beta) signaling in mice lacking the TGF-beta type II receptor gene (Tgfbr2) in their limbs (Tgfbr2(PRX-1KO)). In Tgfbr2(PRX-1KO) mice, the loss of TGF-beta responsiveness resulted in the absence of interphalangeal joints. The Tgfbr2(Prx1KO) joint phenotype is similar to that in patients with symphalangism (SYM1-OMIM185800). By generating a Tgfbr2-green fluorescent protein-beta-GEO-bacterial artificial chromosome beta-galactosidase reporter transgenic mouse and by in situ hybridization and immunofluorescence, we determined that Tgfbr2 is highly and specifically expressed in developing joints. We demonstrated that in Tgfbr2(PRX-1KO) mice, the failure of joint interzone development resulted from an aberrant persistence of differentiated chondrocytes and failure of Jagged-1 expression. We found that TGF-beta receptor II signaling regulates Noggin, Wnt9a, and growth and differentiation factor-5 joint morphogenic gene expressions. In Tgfbr2(PRX-1KO) growth plates adjacent to interphalangeal joints, Indian hedgehog expression is increased, whereas Collagen 10 expression decreased. We propose a model for joint development in which TGF-beta signaling represents a means of entry to initiate the process.

摘要

尽管关节形态发生具有临床意义，但其仍然是一个模糊不清的过程。在本研究中，我们确定了转化生长因子β（TGF-β）信号通路在四肢缺乏TGF-β II型受体基因（Tgfbr2）的小鼠（Tgfbr2(PRX-1KO)）中的作用。在Tgfbr2(PRX-1KO)小鼠中，TGF-β反应性的丧失导致指间关节缺失。Tgfbr2(Prx1KO)的关节表型与并指畸形患者（SYM1-OMIM185800）相似。通过构建Tgfbr2-绿色荧光蛋白-β-GEO-细菌人工染色体-β-半乳糖苷酶报告基因转基因小鼠，并进行原位杂交和免疫荧光实验，我们确定Tgfbr2在发育中的关节中高度特异性表达。我们证明，在Tgfbr2(PRX-1KO)小鼠中，关节中间带发育失败是由于分化软骨细胞异常持续存在以及Jagged-1表达失败所致。我们发现TGF-β受体II信号通路调节Noggin、Wnt9a以及生长和分化因子-5等关节形态发生基因的表达。在与指间关节相邻的Tgfbr2(PRX-1KO)生长板中，印度刺猬蛋白表达增加，而胶原蛋白10表达减少。我们提出了一个关节发育模型，其中TGF-β信号通路是启动该过程的一种途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/043e202abc39/jcb1771105f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/cae853d4cadb/jcb1771105f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/7a707f06bff2/jcb1771105f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/e64d34302f4f/jcb1771105f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/8045d993413c/jcb1771105f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/b6bbcd47a9ff/jcb1771105f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/bd3ae83568db/jcb1771105f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/11cfd7a23691/jcb1771105f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/977acaa5a28a/jcb1771105f08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/5c7e445e606a/jcb1771105f09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/043e202abc39/jcb1771105f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/cae853d4cadb/jcb1771105f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/7a707f06bff2/jcb1771105f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/e64d34302f4f/jcb1771105f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/8045d993413c/jcb1771105f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/b6bbcd47a9ff/jcb1771105f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/bd3ae83568db/jcb1771105f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/11cfd7a23691/jcb1771105f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/977acaa5a28a/jcb1771105f08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/5c7e445e606a/jcb1771105f09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d84d/2064369/043e202abc39/jcb1771105f10.jpg

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