Molecular mechanism of FGF10 signaling in pancreatic development

描述（由申请人提供）：胰腺中FGF 10信号传导的分子机制尚不清楚。FGF 10控制胰腺上皮细胞分裂以及分化。在不存在FGF 10的情况下（fgflO -/-小鼠），胰腺不能形成并且在早期出芽阶段被阻止。在FGF 10水平增加的情况下（pPDX 10-FGF 10 FLAG小鼠），胰腺上皮细胞维持增加的增殖水平，并停滞在未分化状态。后一种效应可以归因于Notch信号传导水平的增加。我们发现Jaggedl和Jagged 2，Notch配体，以前在发育中的胰腺中未被表征，可以解释这一点。这种机制先于Notch参与胰腺终末命运的选择。 在该提案中，我们将解决胰腺发育中FGF 10信号传导的机制基础，并研究该信号传导机制如何控制下游靶基因。我们已经确定Ets-蛋白家族作为FGF 10磷酸化的合理靶点，并且通过几个排除标准对该家族的所有成员进行评估，我们发现Etv-亚家族参与FGF 10信号传导。 我们将在这里的特点的Etv亚家族的选择成员在胰腺细胞分化和胰腺祖细胞扩增过程中的作用。我们还将这些作为FGF 10诱导的MARK磷酸化的靶标和作为胰腺祖细胞中FGF 10靶基因表达的调节剂。为此，我们将进行基因功能的体外和体内测定，包括转基因和靶向突变策略。这项工作对于糖尿病细胞替代来源的产生很重要。

DESCRIPTION (provided by applicant): The molecular mechanism of FGF10 signaling in the pancreas is not understood. FGF10 controls pancreatic epithelial cell division as well as differentiation. In absence of FGF10 (fgflO -/- mice), the pancreas fails to form and is arrested at the early budding stage. In the presence of increased levels of FGF10 (pPDX10-FGF10FLAG mice) the pancreatic epithelium maintains an increased level of proliferation, and becomes arrested in an undifferentiated state. The latter effect can be attributed to increased levels of Notch signaling. We found that Jaggedl and Jagged2, Notch ligands, previously uncharacterized in the developing pancreas, may account for this. This mechanism precedes the later involvement of Notch in selection of pancreatic terminal fates. In this proposal we will address the mechanistic basis of FGFlO-signaling in pancreatic development, and investigate how this signaling mechanism may control downstream target genes. We have identified the Ets-protein family as a plausible target for FGF10 phosphorylation, and through an evaluation of all members of this family by several exclusion criteria, we have found that the Etv-subfamily is involved in FGF10 signaling. We will here characterize the role of select members of the Etv-subfamily in pancreatic cell differentiation and during pancreatic progenitor cell expansion. We will also address these as targets of FGFlO-induced MARK phosphorylation and as regulators of FGF10 target gene expression in pancreatic progenitors. To do this, we will perform in-vitro, and in-vivo assays of gene function, including transgenic and targeted mutation strategies. This work is important in relation to the generation of a cell replacement source for Diabetes.