Specification and Positioning of the Pancreas

描述（由申请人提供）：这项工作的目标是了解胰腺原基在胚胎发生过程中是如何被指定和定位的。我们已经发现，胰腺原基转移到一个更前面的位置在胚胎中的Meis或Pbx家族蛋白被破坏。由于已知Meis和Pbx蛋白作为转录因子如Hox蛋白的辅因子，我们假设内胚层在这些胚胎中经历后转化，并且Meis和Pbx蛋白是转录因子（Hox蛋白或可能的vHnfl同源结构域蛋白）正确指定和定位胰腺原基所需的。为了验证这一假设，我们将首先通过检查在meis或pbx功能被破坏的胚胎中其他内胚层衍生的器官原基是否也向前移位来确定内胚层是否经历了后向转化。然后，我们将确定在前面位置的胰腺命运的诱导是否需要与正常胰腺发育相同的诱导信号。最后，我们将确定在胰腺原基定位过程中哪些蛋白质需要Meis和Pbx辅因子。Hox蛋白是最有可能的候选者，因为它们参与控制外胚层和中胚层的前后模式，但我们最近证明了在MODY5中突变的vHnfl（又名Hnfl 1 β），最近参与早期胰腺发育，结合Meis3和Pbx4，因此我们将探索vHnfl是否参与定位胰腺原基。 胰腺具有多种功能，包括通过产生激素如胰岛素来维持葡萄糖稳态。胰腺缺陷会导致糖尿病等疾病，这些实验的结果将适用于胰腺发育、疾病和治疗的几个方面。首先，他们将揭示胰腺原基是如何被指定和定位的，这将为了解正常和疾病条件下的胰腺发育提供重要信息。其次，他们将揭示胰腺的发展如何可以诱导在异位网站内胚层，以及探索各种内胚层器官原基之间的发展关系。该信息可适用于从胚胎内胚层、从其他器官原基或最终从体外干细胞获得胰腺前体，作为产生用于治疗应用的材料的手段。

DESCRIPTION (provided by applicant): The goal of this work is to understand how the pancreas primordium is specified and positioned during embryogenesis. We have found that the pancreas primordium is shifted to a more anterior position in embryos where Meis or Pbx family proteins are disrupted. Since Meis and Pbx proteins are known to act as cofactors for transcription factors such as Hox proteins, we hypothesize that the endoderm undergoes a posterior transformation in these embryos and that Meis and Pbx proteins are required for transcription factors (Hox proteins or perhaps the vHnfl homeodomain protein) to correctly specify and position the pancreas primordium. To test this hypothesis we will first determine if the endoderm undergoes a posterior transformation by examining whether other endoderm-derived organ primordia are also shifted anteriorly in embryos with disrupted meis or pbx function. We will then determine if induction of pancreatic fates at anterior positions requires the same inductive signals as normal pancreas development. Lastly, we will determine which proteins require Meis and Pbx cofactors during positioning of the pancreas primordium. Hox proteins are the most likely candidates since they have been implicated in controlling anteroposterior patterning in the ectoderm and mesoderm, but we have recently demonstrated that vHnfl (a.k.a Hnfl1beta), which is mutated in MODY5 and has recently been implicated in early pancreas development, binds Meis3 and Pbx4 and we will therefore explore whether vHnfl is involved in positioning the pancreas primordium. The pancreas serves several functions, including maintenance of glucose homeostasis via the production of hormones such as insulin. Pancreatic defects cause diseases such as diabetes and the results from these experiments will be applicable to several aspects of pancreas development, disease and treatment. First, they will reveal how the pancreas primordium is specified and positioned, which will provide information important in understanding pancreas development under both normal and disease conditions. Second, they will reveal how pancreas development can be induced at ectopic sites in the endoderm, as well as explore the developmental relationship between the various endodermal organ primordia. This information may be applicable to deriving pancreas precursors from embryonic endoderm, from other organ primordia, or ultimately from stem cells in vitro, as a means of generating material for therapeutic applications.