title: Growth Factor Independence-1 (Gfi1) Is Required for Pancreatic Acinar Unit Formation and Centroacinar Cell Differentiation.
abstract: OBJECTIVE
  The genetic specification of the compartmentalized pancreatic acinar/centroacinar unit is poorly understood. Growth factor independence-1 (Gfi1) is a zinc finger transcriptional repressor that regulates hematopoietic stem cell maintenance, pre-T-cell differentiation, formation of granulocytes, inner ear hair cells, and the development of secretory cell types in the intestine. AsGFI1/Gfi1is expressed in human and rodent pancreas, we characterized the potential function ofGfi1in mouse pancreatic development.
  
  
  METHODS
  Gfi1knockout mice were analyzed at histological and molecular levels, including qRT-PCR, in situ hybridization, immunohistochemistry, and electron microscopy.
  
  
  RESULTS
  Loss ofGfi1impacted formation and structure of the pancreatic acinar/centroacinar unit. Histologic and ultrastructural analysis ofGfi1-null pancreas revealed specific defects at the level of pancreatic acinar cells as well as the centroacinar cells (CACs) inGfi1-/-mice when compared with wild-type littermates. Pancreatic endocrine differentiation, islet architecture, and function were unaffected. Organ domain patterning and the formation of ductal cells occurred normally during the murine secondary transition (E13.5-E14.5) in theGfi1-/-pancreas. However, at later gestational time points (E18.5), expression of cellular markers for CACs was substantially reduced inGfi1-/-mice, corroborated by electron microscopy imaging of the acinar/centroacinar unit. The reduction in CACs was correlated with an exocrine organ defect. Postnatally,Gfi1deficiency resulted in severe pancreatic acinar dysplasia, including loss of granulation, autolytic vacuolation, and a proliferative and apoptotic response.
  
  
  CONCLUSIONS
  Gfi1plays an important role in regulating the development of pancreatic CACs and the function of pancreatic acinar cells.
authors.affiliation: Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Qu
authors.affiliation: Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio; Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Nyeng
authors.affiliation: Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Fan
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio.
authors.forename: Jorge
authors.initials: J
authors.lastname: Dorantes
authors.affiliation: Cleveland Clinic, Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio.
authors.forename: Jan
authors.initials: J
authors.lastname: Jensen
keywords: BPL, Bauhinia purpurea lectin; BrdU, bromodeoxyuridine; CACs, centroacinar cells; Centroacinar Cells; Claudin 10; DIG, digoxigenin; EM, electron micrographs; Gfi1, growth factor independence-1; Growth Factor Independence-1 (Gfi1); PBS, phosphate-buffered saline; SD, standard deviation; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; TipPC, tip progenitor cells; TrPC, trunk progenitor cells; WT, wild type; qRT-PCR, quantitative real-time polymerase chain reaction; rER, rough endoplasmic reticulum