Tefft Denise, De Langhe Stijn P, Del Moral Pierre-Marie, Sala Frederic, Shi Wei, Bellusci Saverio, Warburton David
Developmental Biology Program, Department of Surgery, USC Keck School of Medicine and the Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Dev Biol. 2005 Jun 15;282(2):422-31. doi: 10.1016/j.ydbio.2005.03.022.
Branching morphogenesis of many organs, including the embryonic lung, is a dynamic process in which growth factor mediated tyrosine kinase receptor activation is required, but must be tightly regulated to direct ramifications of the terminal branches. However, the specific regulators that modulate growth factor signaling downstream of the tyrosine kinase receptor remain to be determined. Herein, we demonstrate for the first time an important function for the intracellular protein tyrosine phosphatase Shp2 in directing embryonic lung epithelial morphogenesis. We show that Shp2 is specifically expressed in embryonic lung epithelial buds, and that loss of function by the suppression of Shp2 mRNA expression results in a 53% reduction in branching morphogenesis. Furthermore, by intra-tracheal microinjection of a catalytically inactive adenoviral Shp2 construct, we provide direct evidence that the catalytic activity of Shp2 is required for proper embryonic lung branch formation. We demonstrate that Shp2 activity is required for FGF10 induced endodermal budding. Furthermore, a loss of Shp2 catalytic activity in the embryonic lung was associated with a reduction in ERK phosphorylation and epithelial cell proliferation. However, epithelial cell differentiation was not affected. Our results show that the protein tyrosine phosphatase Shp2 plays an essential role in modulating growth factor mediated tyrosine kinase receptor activation in early embryonic lung branching morphogenesis.
包括胚胎肺在内的许多器官的分支形态发生是一个动态过程，在此过程中，生长因子介导的酪氨酸激酶受体激活是必需的，但必须受到严格调控以引导终末分支的分支。然而，调节酪氨酸激酶受体下游生长因子信号传导的具体调节因子仍有待确定。在此，我们首次证明细胞内蛋白酪氨酸磷酸酶Shp2在引导胚胎肺上皮形态发生中具有重要功能。我们表明，Shp2在胚胎肺上皮芽中特异性表达，并且通过抑制Shp2 mRNA表达导致功能丧失，使分支形态发生减少53%。此外，通过气管内显微注射无催化活性的腺病毒Shp2构建体，我们提供了直接证据表明Shp2的催化活性对于正确的胚胎肺分支形成是必需的。我们证明Shp2活性对于FGF10诱导的内胚层出芽是必需的。此外，胚胎肺中Shp2催化活性的丧失与ERK磷酸化和上皮细胞增殖的减少有关。然而，上皮细胞分化未受影响。我们的结果表明，蛋白酪氨酸磷酸酶Shp2在早期胚胎肺分支形态发生中调节生长因子介导的酪氨酸激酶受体激活方面发挥着重要作用。
