Specification and Positioning of the Pancreas

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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.