Korostylev Alexander, Worzfeld Thomas, Deng Suhua, Friedel Roland H, Swiercz Jakub M, Vodrazka Peter, Maier Viola, Hirschberg Alexandra, Ohoka Yoshiharu, Inagaki Shinobu, Offermanns Stefan, Kuner Rohini
Pharmacology Institute, Im Neuenheimer Feld 366, University of Heidelberg, 69120 Heidelberg, Germany.
Development. 2008 Oct;135(20):3333-43. doi: 10.1242/dev.019760. Epub 2008 Sep 17.
Semaphorins and their receptors, plexins, carry out important functions during development and disease. In contrast to the well-characterized plexin A family, however, very little is known about the functional relevance of B-type plexins in organogenesis, particularly outside the nervous system. Here, we demonstrate that plexin B1 and its ligand Sema4d are selectively expressed in epithelial and mesenchymal compartments during key steps in the genesis of some organs. This selective expression suggests a role in epithelial-mesenchymal interactions. Importantly, using the developing metanephros as a model system, we have observed that endogenously expressed and exogenously supplemented Sema4d inhibits branching morphogenesis during early stages of development of the ureteric collecting duct system. Our results further suggest that the RhoA-ROCK pathway, which is activated downstream of plexin B1, mediates these inhibitory morphogenetic effects of Sema4d and suppresses branch-promoting signalling effectors of the plexin B1 signalling complex. Finally, mice that lack plexin B1 show early anomalies in kidney development in vivo. These results identify a novel function for plexin B1 as a negative regulator of branching morphogenesis during kidney development, and suggest that the Sema4d-plexin B1 ligand-receptor pair contributes to epithelial-mesenchymal interactions during organogenesis via modulation of RhoA signalling.
信号素及其受体丛状蛋白在发育和疾病过程中发挥着重要作用。然而，与特征明确的丛状蛋白A家族不同，关于B型丛状蛋白在器官发生中的功能相关性，尤其是在神经系统之外的功能相关性，人们了解甚少。在此，我们证明丛状蛋白B1及其配体信号素4D在某些器官发生的关键步骤中在上皮和间充质区室中选择性表达。这种选择性表达表明其在上皮-间充质相互作用中发挥作用。重要的是，利用发育中的后肾作为模型系统，我们观察到内源性表达和外源性补充的信号素4D在输尿管集合管系统发育的早期阶段抑制分支形态发生。我们的结果进一步表明，在丛状蛋白B1下游被激活的RhoA-ROCK途径介导了信号素4D的这些抑制性形态发生效应，并抑制了丛状蛋白B1信号复合物的促进分支的信号效应器。最后，缺乏丛状蛋白B1的小鼠在体内肾脏发育中表现出早期异常。这些结果确定了丛状蛋白B1作为肾脏发育过程中分支形态发生的负调节因子的新功能，并表明信号素4D-丛状蛋白B1配体-受体对通过调节RhoA信号传导在器官发生过程中促进上皮-间充质相互作用。
