title: Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Surgery, 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: Michiya
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Mami
authors.initials: M
authors.lastname: Terao
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Mikio
authors.initials: M
authors.lastname: Hoshino
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
mesh_terms: D000818:Animals; D049628:Body Size; D002455:Cell Division / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology*; D004386:Duodenum / Q000166:cytology; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D018149:Glucose Intolerance / Q000235:genetics / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000002:abnormalities* / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046790:Pancreas, Exocrine / Q000002:abnormalities / Q000473:pathology / Q000502:physiology; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; C062602:transcription factor PTF1