title: Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas.
abstract: 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.
authors.affiliation: Department of Surgery and Surgical Basic Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukuda
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Furuyama
authors.forename: Sota
authors.initials: S
authors.lastname: Kodama
authors.forename: Masashi
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuhara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Koizumi
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Boyer
authors.forename: Koji
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001652:Bile Ducts / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology; D019070:Cell Lineage; D002828:Choristoma / Q000378:metabolism / Q000473:pathology*; D004378:Duodenal Diseases / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D004707:Endoderm; D041981:Gastrointestinal Tract / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000473:pathology / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D022661:RNA, Untranslated; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C489734:Hes1 protein, mouse; C407737:Neurog3 protein, mouse; C062602:transcription factor PTF1