Role of PI 3-kinase and PIP3 in submandibular gland branching morphogenesis
Role of PI 3-kinase and PIP3 in submandibular gland branching morphogenesis
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DOI：
10.1016/s0012-1606(02)00047-7
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发表时间：
2003-03-01
影响因子：
2.7
通讯作者：
Yamada, KM
中科院分区：
文献类型：
--
作者：
Larsen, M;Hoffman, MP;Yamada, KM
小鼠颌下腺（SMG）上皮在胚胎发育过程中经历了广泛的形态发生分支，这是其腺结构建立的第一步。然而，SMG分支形态发生所需的特定信号通路尚不清楚。通过E13小鼠SMG器官培养，我们发现磷脂酰肌醇3-激酶（PI 3-激酶）抑制剂、wortmannin和LY294002可以显著抑制SMG的分支形态发生。剥去间质的上皮雏形分支形态发生同样受到抑制，表明PI 3-激酶抑制剂直接作用于上皮。免疫染色和Western分析显示pi3 -激酶p85亚型在上皮中的表达水平高于在间质中的表达水平。Western分析显示，pi3激酶的靶点Akt/protein kinase B （PKB）在pi3激酶抑制剂的作用下，丝氨酸位点（473）的磷酸化降低。pi3 -激酶的主要脂质产物，磷脂酰肌醇3,4,5-三磷酸（PIP3），在存在pi3 -激酶抑制剂的情况下，通过膜转运载体外源性添加到SMG中，并被发现刺激裂缝形成，这是分支形态发生的第一步。综上所述，这些数据表明PI 3-激酶通过PIP3通路在小鼠SMG上皮分支形态发生的调控中发挥作用。(C) 2003 Elsevier Science（美国）版权所有。
The mouse submandibular gland (SMG) epithelium undergoes extensive morphogenetic branching during embryonic development as the first step in the establishment of its glandular structure. However, the specific signaling pathways required for SMG branching morphogenesis are not well understood. Using E13 mouse SMG organ cultures, we showed that inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), wortmannin and LY294002, substantially inhibited branching morphogenesis in SMG. Branching morphogenesis of epithelial rudiments denuded of mesenchyme was inhibited similarly, indicating that PI 3-kinase inhibitors act directly on the epithelium. Immunostaining and Western analysis demonstrated that the p85 isoform of PI 3-kinase is expressed in epithelium at levels higher than in the mesenchyme. A target of PI 3-kinase, Akt/protein kinase B (PKB), showed decreased phosphorylation at Ser(473) by Western analysis in the presence of PI 3-kinase inhibitors. The major lipid product of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (PIP3), was added exogenously to SMG via a membrane-transporting carrier in the presence of PI 3-kinase inhibitors and was found to stimulate cleft formation, the first step of branching morphogenesis. Together, these data indicate that PI 3-kinase plays a role in the regulation of epithelial branching morphogenesis in mouse SMG acting through a PIP3 pathway. (C) 2003 Elsevier Science (USA). All rights reserved.