Diabetes Caused by Elastase-Cre-Mediated Pdx1 Inactivation in Mice.

Endocrine and exocrine pancreas tissues are both derived from the posterior foregut endoderm, however, the interdependence of these two cell types during their formation is not well understood. In this study, we generated mutant mice, in which the exocrine tissue is hypoplastic, in order to reveal a possible requirement for exocrine pancreas tissue in endocrine development and/or function. Since previous studies showed an indispensable role for Pdx1 in pancreas organogenesis, we used Elastase-Cre-mediated recombination to inactivate Pdx1 in the pancreatic exocrine lineage during embryonic stages. Along with exocrine defects, including impaired acinar cell maturation, the mutant mice exhibited substantial endocrine defects, including disturbed tip/trunk patterning of the developing ductal structure, a reduced number of Ngn3-expressing endocrine precursors, and ultimately fewer ß cells. Notably, postnatal expansion of the endocrine cell content was extremely poor, and the mutant mice exhibited impaired glucose homeostasis. These findings suggest the existence of an unknown but essential factor(s) in the adjacent exocrine tissue that regulates proper formation of endocrine precursors and the expansion and function of endocrine tissues during embryonic and postnatal stages.

Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine.

The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.

Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice.

OBJECTIVE: Most pancreatic endocrine cells derive from Ptf1a-expressing progenitor cells. In humans, nonsense mutations in Ptf1a have recently been identified as a cause of permanent neonatal diabetes associated with pancreatic agenesis. The death of Ptf1a-null mice soon after birth has not allowed further insight into the pathogenesis of the disease; it is therefore unclear how much pancreatic endocrine function is dependent on Ptf1a in mammals. This study aims to investigate gene-dosage effects of Ptf1a on pancreas development and function in mice. RESEARCH DESIGN AND METHODS: Combining hypomorphic and null alleles of Ptf1a and Cre-mediated lineage tracing, we followed the cell fate of reduced Ptf1a-expressing progenitors and analyzed pancreas development and function in mice. RESULTS: Reduced Ptf1a dosage resulted in pancreatic hypoplasia and glucose intolerance with insufficient insulin secretion in a dosage-dependent manner. In hypomorphic mutant mice, pancreatic bud size was small and substantial proportions of pancreatic progenitors were misspecified to the common bile duct and duodenal cells. Growth with branching morphogenesis and subsequent exocrine cytodifferentiation was reduced and delayed. Total beta-cell number was decreased, proportion of non-beta islet cells was increased, and alpha-cells were abnormally intermingled with beta-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis. CONCLUSIONS-The dosage of Ptf1a is crucial for pancreas specification, growth, total beta-cell number, islet morphogenesis, and endocrine function. Some neonatal diabetes may be caused by mutation or single nucleotide polymorphisms in the Ptf1a gene that reduce gene expression levels.

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

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.

Loss of the major duodenal papilla results in brown pigment biliary stone formation in pdx1 null mice.

BACKGROUND & AIMS: Pdx1 plays a pivotal role in pancreas organogenesis and specification of some types of cells in the duodenum and antral stomach. However, its expression is not restricted to pancreas, duodenum, and antral stomach but is also found in the common bile duct during embryogenesis. This study aimed to elucidate the role of Pdx1 in the development of the common bile duct, major duodenal papilla, and duodenum. METHODS: Expression pattern of pdx1 during embryogenesis and the morphology of the common bile duct, major duodenal papilla, and duodenum in pdx1 null mice were analyzed. RESULTS: The major duodenal papilla, peribiliary glands, and mucin-producing cells in the common bile duct were not formed in pdx1 null mice. Pdx1 null mice had shorter periampullary duodenal villi than wild-type mice at postnatal stages associated with reduced cell proliferation and increased apoptosis of the duodenal epithelial cells. Loss of the major duodenal papilla allowed duodeno-biliary reflux and bile infection, resulting in the formation of brown pigment biliary stones in pdx1 null mice, and antibiotics treatment significantly reduced the incidence of biliary stone formation. CONCLUSIONS: Pdx1 is required for proper development of the major duodenal papilla, peribiliary glands, and mucin-producing cells in the common bile duct and for maintenance of the periampullary duodenal epithelial cells during perinatal period. Bile infection because of loss of the major duodenal papilla plays a significant role in the formation of brown pigment biliary stones in pdx1 null mice.