title: Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation ofHhexin Mice.
abstract: Perturbations in pancreatic ductal bicarbonate secretion cause chronic pancreatitis. The physiologic mechanism of ductal secretion is known, but its transcriptional control is not. We determine the role of the transcription factor hematopoietically expressed homeobox protein (Hhex) in ductal secretion and pancreatitis.
  
  
  
  We derived mice with pancreas-specific, CremediatedHhexgene ablation to determine the requirement ofHhexin the pancreatic duct in early life and in adult stages. Histologic and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells were isolated to discover differentially expressed transcripts upon acuteHhexablation on a cell autonomous level.
  
  
  
  Hhexprotein was detected throughout the embryonic and adult ductal trees. Ablation ofHhexin pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis.Hhexablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia in young mice did not result from perturbation of expression of Hnf6, Hnf1β, or the primary cilia genes. RNA-seq analysis ofHhex-ablated pancreatic primary ductal cells showed mRNA levels of the G-protein coupled receptor natriuretic peptide receptor 3 (Npr3), implicated in paracrine signaling, up-regulated by 4.70-fold.
  
  
  
  AlthoughHhexis dispensable for ductal cell function in the adult, ablation ofHhexin pancreatic progenitors results in pancreatitis. Our data highlight the critical role ofHhexin maintaining ductal homeostasis in early life and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis.
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferreira
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: McKenna
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Basil
authors.initials: B
authors.lastname: Bakir
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Buza
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Bogue
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
keywords: Npr3; Pancreatic Ducts; Primary Cilia