Abstract
BackgroundIn the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated.Methodology/Principal FindingsWe exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development.Conclusions/SignificanceThis study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature β cell function.
Highlights
Despite the recent success with islet transplantation as a treatment for replacing insulin-producing b cells lost in individuals with Type 1 diabetes [1], the relative shortage of donor tissue necessitates the development of in vitro systems to grow functional islets
Studies by various laboratories over the past several years have resulted in the identification of several transcription factors that function in normal pancreatic/islet cell development; much less is known about the cell surface or extracellular components involved in islet formation and function
We found that maintaining Hepatic nuclear factor 6 (Hnf6) expression in islets resulted in a host of morphological and functional deficiencies, including a scattering of cell types within the islets, abnormal islet size, decreased insulin secretion, and a block to b cell maturation (Figure 1; [15,22])
Summary
Despite the recent success with islet transplantation as a treatment for replacing insulin-producing b cells lost in individuals with Type 1 diabetes [1], the relative shortage of donor tissue necessitates the development of in vitro systems to grow functional islets. In the early stages of islet morphogenesis (around e17.5), these hormone-expressing endocrine cells can be found in clusters closely associated with the pancreatic ductal epithelium from which they originate [7,8,9,10]. In 2000, Cirulli et al demonstrated that avb and avb integrins could mediate the adhesion and migration of putative endocrine precursors [12] Despite these and other studies, many of the processes involved in endocrine cell migration/delamination and islet morphogenesis are not yet well understood. Previous studies have shown that transgenic over-expression of the transcription factor Hnf in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf causes defects in islet morphogenesis have yet to be elucidated
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