The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity.
The pancreas is a complex organ that consists of separate endocrine and exocrine cell compartments. Although great strides have been made in identifying regulatory factors responsible for endocrine pancreas formation, the molecular regulatory circuits that control exocrine pancreas properties are just beginning to be elucidated. In an effort to identify genes involved in exocrine pancreas function, we have examined Mist1, a basic helix-loop-helix transcription factor expressed in pancreatic acinar cells. Mist1-null (Mist1(KO)) mice exhibit extensive disorganization of exocrine tissue and intracellular enzyme activation. The exocrine disorganization is accompanied by increases in p8, RegI/PSP, and PAP1/RegIII gene expression, mimicking the molecular changes observed in pancreatic injury. By 12 m, Mist1(KO) mice develop lesions that contain cells coexpressing acinar and duct cell markers. Analysis of the factors involved in cholecystokinin (CCK) signaling reveal inappropriate levels of the CCK receptor A and the inositol-1,4,5-trisphosphate receptor 3, suggesting that a functional defect exists in the regulated exocytosis pathway of Mist1(KO) mice. Based on these observations, we propose that Mist1(KO) mice represent a new genetic model for chronic pancreas injury and that the Mist1 protein serves as a key regulator of acinar cell function, stability, and identity.
Pin
C L
CL
Department of Paediatrics, Child Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada.
Rukstalis
J M
JM
Johnson
C
C
Konieczny
S F
SF
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002766:Cholecystokinin / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D005314:Embryonic and Fetal Development; D005260:Female; D018257:Helix-Loop-Helix Motifs; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000166:cytology* / Q000196:embryology / Q000293:injuries; D000073718:Pancreatitis-Associated Proteins; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin
D051792:Basic Helix-Loop-Helix Proteins; D002766:Cholecystokinin; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D000073718:Pancreatitis-Associated Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; C491312:Bhlha15 protein, mouse; C495267:CTNNB1 protein, mouse; C000612141:REG3A protein, human; C569043:Tjp1 protein, mouse