Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT).
Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT).
复制标题
DOI：
--
复制
发表时间：
2004
影响因子：
3
通讯作者：
A. Nawshad;D. Lagamba;E. Hay
中科院分区：
文献类型：
--
作者：
A. Nawshad;D. Lagamba;E. Hay
内缘上皮（MEE）缝的形成是腭裂发育的关键步骤。相反的架子首先通过粘附连接相互粘附，然后通过MEE中的桥粒相互粘附。上皮间充质转化（epithelial mesenchymal transformation， EMT）使结缔组织在上颚形成汇合处，MEE缝随之消失。腭裂具有多因素的病因，通常包括对腭架的粘附失败和/或MEE的EMT。在这篇综述中，我们首先讨论TGFbeta生物学，包括TGFbeta亚型、受体、下游转录因子、内体和信号通路的功能。TGFbeta家族的不同亚型在调节腭发育的各个方面发挥重要作用。TGFbeta1和TGFbeta2参与生长，但由TGFbeta3调控MEE向间质转化，实现腭合流。它的缺失导致腭裂。因此，了解TGFbeta家族信号传导对于制定治疗策略至关重要。由于TGFbeta3及其下游靶标LEF1在上皮转化中起主要作用，因此确定它们在腭EMT中使用的信号通路非常重要。在这里，我们将详细讨论TGFbeta3信号响应下腭缝消失的机制，包括生长和凋亡的作用（如果有的话），以及EMT在MEE成功粘附和缝形成中的作用。我们也回顾了最近的证据，TGFbeta3在腭EMT期间使用Smad2和4而不是β - catenin来激活LEF1。据报道，TGFbeta1在体外使用RhoA或map激酶使用非smad信号，但这些不参与腭EMT的原位激活。本综述的主要目的是记录TGFbeta用于腭EMT的遗传机制，并将其与其他地方使用的EMT机制进行比较。
Formation of the medial edge epithelial (MEE) seam by fusing the palatal shelves is a crucial step of palate development. The opposing shelves adhere to each other at first by adherens junctions, then by desmosomes in the MEE. The MEE seam disappears by epithelial mesenchymal transformation (EMT), which creates confluence of connective tissue across the palate. Cleft palate has a mutifactorial etiology that often includes failure of adherence of apposing individual palatal shelves and/or EMT of the MEE. In this review, we first discuss TGFbeta biology, including functions of TGFbeta isoforms, receptors, down stream transcription factors, endosomes, and signalling pathways. Different isoforms of the TGFbeta family play important roles in regulating various aspects of palate development. TGFbeta1 and TGFbeta2 are involved in growth, but it is TGFbeta3 that regulates MEE transformation to mesenchyme to bring about palatal confluence. Its absence results in cleft palate. Understanding of TGFbeta family signalling is thus essential for development of therapeutic strategies. Because TGFbeta3 and its downstream target, LEF1, play the major role in epithelial transformation, it is important to identify the signalling pathways they use for palatal EMT. Here, we will discuss in detail the mechanisms of palatal seam disappearance in response to TGFbeta3 signalling, including the roles, if any, of growth and apoptosis, as well as EMT in successful MEE adherence and seam formation. We also review recent evidence that TGFbeta3 uses Smad2 and 4 during palatal EMT, rather than beta-Catenin, to activate LEF1. TGFbeta1 has been reported to use non-Smad signalling using RhoA or MAPKinases in vitro, but these are not involved in activation of palatal EMT in situ. A major aim of this review is to document the genetic mechanisms that TGFbeta uses to bring about palatal EMT and to compare these with EMT mechanisms used elsewhere.