The pancreas emerges independently from dorsal and ventral domains of embryonic gut endoderm. Gene inactivation experiments in mice have identified factors required for dorsal pancreas development, but factors that initiate the ventral pancreas have remained elusive. In this study, we investigated the hypothesis that the emergence of the ventral pancreas is related to the emergence of the liver. We find that the liver and ventral pancreas are specified at the same time and in the same general domain of cells. Using embryo tissue explantation experiments, we find that the default fate of the ventral foregut endoderm is to activate the pancreas gene program. FGF signalling from the cardiac mesoderm diverts this endoderm to express genes for liver instead of those for pancreas. No evidence was found to indicate that the cell type choice for pancreas or liver involves a selection for growth or viability. Cardiac mesoderm or FGF induces the local expression of sonic hedgehog, which in turn is inhibitory to pancreas but not to liver. The bipotential precursor cell population for pancreas and liver in embryonic development and its fate selection by FGF has features that appear to be recapitulated in the adult pancreas and are reflected in the evolution of these organs.

A bipotential precursor population for pancreas and liver within the embryonic endoderm.

Genetic analysis, embryonic tissue explantation and in vivo chromatin studies have together identified the distinct regulatory steps that are necessary for the development of endoderm into a bud of liver tissue and, subsequently, into an organ. In this review, I discuss the acquisition of competence to express liver-specific genes by the endoderm, the control of early hepatic growth, the coordination of hepatic and vascular development and the cell differentiation that is necessary to generate a functioning liver. The regulatory mechanisms that underlie these phases are common to the development of many organ systems and might be recapitulated or disrupted during stem-cell differentiation and adult tissue pathogenesis.

Regulatory phases of early liver development: paradigms of organogenesis.

The biliary system, pancreas and liver all develop from the nearby foregut at almost the same time in mammals The molecular mechanisms that determine the identity of each organ in this complex area are unknown Hes1 encodes the basic helix-loop-helix protein Hes1 (ref 1), which represses positive basic helix-loop-helix genes such as Neurog3 (ref 3) Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway Hes1 operates as a general negative regulator of endodermal endocrine differentiation, and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation Mutations in JAG1, encoding a Notch ligand, cause the Alagille syndrome in humans, characterized by poor development of the biliary system, suggesting that the Notch pathway is also involved in normal biliary development Here we show that Hes1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts Biliary epithelium in Hes1-/- mice ectopically expresses the proendocrine gene Neurog3 (refs 12,13), differentiates into endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts Thus, biliary epithelium has the potential for pancreatic differentiation and Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3

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Conversion of biliary system to pancreatic tissue in Hes1-deficient mice.

Hepatocyte differentiation: from the endoderm and beyond

Ectopic pancreas is a developmental anomaly occasionally found in humans. Hes1, a main effector of Notch signaling, regulates the fate and differentiation of many cell types during development. To gain insights into the role of the Notch pathway in pancreatic fate determination, we combined the use of Hes1-knockout mice and lineage tracing employing the Cre/loxP system to specifically mark pancreatic precursor cells and their progeny in Ptf1a-cre and Rosa26 reporter mice. We show that inactivation of Hes1 induces misexpression of Ptf1a in discrete regions of the primitive stomach and duodenum and throughout the common bile duct. All ectopic Ptf1a-expressing cells were reprogrammed, or transcommitted, to multipotent pancreatic progenitor status and subsequently differentiated into mature pancreatic exocrine, endocrine, and duct cells. This process recapitulated normal pancreatogenesis in terms of morphological and genetic features. Furthermore, analysis of Hes1/Ptf1a double mutants revealed that ectopic Ptf1a-cre lineage-labeled cells adopted the fate of region-appropriate gut epithelium or endocrine cells similarly to Ptf1a-inactivated cells in the native pancreatic buds. Our data demonstrate that the Hes1-mediated Notch pathway is required for region-appropriate specification of pancreas in the developing foregut endoderm through regulation of Ptf1a expression, providing novel insight into the pathogenesis of ectopic pancreas development in a mouse model.

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Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas

The development of the adult endocrine pancreas was followed throughout metamorphosis in the sea lamprey using electron microscopy and immunocytochemistry. It was discovered that the caudal pancreas develops from the larval extrahepatic common bile duct through the process of transdifferentiation (dedifferentiation/redifferentiation). Early in metamorphosis the bile duct epithelial cells possess large vacuoles, resembling autophagic vacuoles, containing recognizable cell material. There is a loss of the large bundles of intermediate filaments characteristic of the larval bile duct epithelium. These same cells are then seen to contain granules immunoreactive for insulin. Pancreatic islets develop within the base of the bile duct epithelium from these transdifferentiated cells and migrate into the surrounding connective tissue to form the caudal pancreas. The cranial pancreas was found to develop from the epithelia lining the developing adult diverticulum and anterior intestine in a similar fashion as those in the larva. The second cell type to appear in either portion of the developing pancreas is similar to the third cell type of the adult: cells immunoreactive for somatostatin do not appear until late in metamorphosis in either region. © 1993 Wiley-Liss Inc.

Development of the adult endocrine pancreas during metamorphosis in the sea lamprey, Petromyzon marinus L. II. Electron microscopy and immunocytochemistry.

The results of this study were found to support the hypothesis put forth by Boenig (Z. Mikrosk-Anat. Forsch., 17:125–184, 1929) that the caudal pancreas of adult lamprey develops from the epithelium of the extrahepatic common bile duct in that the bile duct cells were found to undergo a great proliferation during the early stages of metamorphosis, with a large number of the cells incorporating 3H-thymidine. If the bile duct degenerated as suggested by Barrington (The Biology of Lampreys. Academic Press, London, pp. 135–169, 1972), this uptake would not be expected. The cranial pancreas was determined to develop in a similar manner to the larval islets, with formation of the islets taking place within the intestinal/diverticular epithelium. The newly formed islets would migrate into the surrounding connective tissue. During the later stages of metamorphosis a small number of cells was found to incorporate the tritiated thymidine within mature islets. © 1993 Wiley-Liss Inc.

W. M. Elliott

Papers

Development of the adult endocrine pancreas during metamorphosis in the sea lamprey, Petromyzon marinus L. II. Electron microscopy and immunocytochemistry.

Development of the adult endocrine pancreas during metamorphosis in the sea lamprey, Petromyzon marinus L. I. Light microscopy and autoradiography