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The ventral pancreas, biliary system and liver arise from the posterior ventral foregut, but the cell-intrinsic pathway by which these organ lineages are separated is not known. Here we show that the extrahepatobiliary system shares a common origin with the ventral pancreas and not the liver, as previously thought.
These pancreatobiliary progenitor cells co-express the transcription factors PDX1 and Sox17 at e8.5, and their segregation into a PDX1+ ventral pancreas and a Sox17+ biliary primordium is Sox17-dependent. Deletion of Sox17 at e8.5 results in the loss of biliary structures and ectopic pancreatic tissue in the liver bud and common duct, while Sox17 overexpression suppresses pancreas development and promotes ectopic biliary-like tissue throughout the PDX1+ domain. Restricting Sox17+ biliary progenitor cells to the ventral region of the gut requires the Notch effector Hes1.
Our results highlight the role of Sox17 and Hes1 in patterning and morphogenetic segregation of ventral foregut lineages.
The pancreas is a vital, endodermally derived organ that regulates glucose homeostasis and digestion. To investigate molecular pathways underlying the development of the pancreas, we used transcriptional profiling to identify the genes expressed during endocrine pancreas development.
We focused our analyses on four biologically significant stages of pancreas development:
We have used GeneSpring and Resolver clustering analysis software to identify known and novel genes that are temporally regulated during endocrine development, as well as genes that spatially define these cells from their neighbors.
The above studies demonstrated that components of the Wnt pathway are expressed during pancreas development. In particular, several Wnt receptors are expressed in the nonendocrine population of cells.
To study the role of Wnt signaling in pancreas development, in collaboration with Andy Lowy at the University of Cincinnati (now at University of San Diego), the Wnt effector protein, beta-catenin, was knocked out in the developing pancreas. Animals lacking beta-catenin in the developing pancreas have no remarkable defects in endocrine pancreas development; however exocrine development is profoundly impaired. Microarray analyses of e14.5 and e16.5 pancreata lacking beta-catenin (in collaboration with Bruce Aronow, Cincinnati Children’s) indicated that exocrine cells are specified, but exocrine progenitor cells fail to proliferate and expand and prematurely differentiate. These data indicate that beta-catenin / Wnt signaling is required for expansion and maintenance of exocrine progenitor cells during development.
Spence JR, Lange AW, Lin SC, Kaestner KH, Lowy AM, Kim I, Whitsett JA, Wells JM. Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev. Cell. 17(1):62-74. Jul, 2009.
Wells JM, Esni F, Boivin GP, Aronow BJ, Stuart W, Combs C, Sklenka A, Leach SD, Lowy AM. Wnt/beta-catenin is required for development of the exocrine pancreas. BMC Dev Biol. 7:4. 2007.
Serls AE, Doherty S, Parvatiyar P,Wells JM, Deutsch GH. Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development. 132:35-47. 2005.
*Gu G, *Wells JM, Dombkowski D, Preffer F, Aronow B, Melton DA. Global expression analysis of gene regulatory pathways during endocrine pancreas development. Development. 131:165-79. 2004. *These authors contributed equally and are listed alphabetically.
Wells JM. Genes expressed in the developing endocrine pancreas and their importance for stem cell and diabetes research. Diabetes Metab Res Rev. 19:191-201. 2003.
This image from Spence et al. shows a section through the developing pancreas and biliary system of an E10 mouse embryo. The pancreas (Pdx1 – green) and biliary tree (Sox17 – blue) derive from a common pool of ventral foregut progenitor cells. Segregation of these organ lineages depends on Sox17 and Notch signaling (Hes1 – red). The image was acquired using a Zeiss confocal microscope.
Cover image used in Developmental Cell.
This image from Spence et al. shows a section through the duodenum and caudal stomach of an E16.5 mouse embryo in which Sox17 was ectopically expressed in the Pdx1 domain of the gut during early embryogenesis (E9-10.5). Sox17 is required for normal development of the extrahepatic biliary ducts, and its misexpression leads to the development of ectopic ductal tissue (HNF6 – green) and loss of duodenal (HNF4alpha – red) and pancreatic tissue. Nuclei are counterstained with TO-PRO-3 (blue). The image was acquired using a Zeiss confocal microscope.
Genes expressed during different stages of developing endocrine pancreas. mRNA from prepancreatic (e7.5) endoderm, early e10.5 pancreas that express Pdx-GFP, endocrine progenitor cells (e13.5 ngn3-GFP), or adult islets of Langerhans were isolated and used to probe Affymetrix chips. Of ~13,000 genes on the Affymetrix chip, we have identified 270 genes that are enriched in endoderm. The expression of 65 of these was verified by RT-PCR, and their in vivo expression is being analyzed by in situ hybridization of e7.5 embryos.
Microarray analysis of beta-catenin-deficient embryonic pancreas.
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