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The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity.

Pin CL, Rukstalis JM, Johnson C, Konieczny SF - J. Cell Biol. (2001)

Bottom Line: 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.The exocrine disorganization is accompanied by increases in p8, RegI/PSP, and PAP1/RegIII gene expression, mimicking the molecular changes observed in pancreatic injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Child Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada.

ABSTRACT
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- (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.

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Mist1 is expressed specifically in acinar cells during pancreatic development. (A) Immunohistochemistry using a Mist1-specific antibody reveals nuclear expression in putative acinar cells surrounding duct tissue (arrows) at E14.5. (B) By postnatal day 1 (PN1), Mist1 expression is wide spread in the pancreas, remaining exclusively in acinar cells. (C–H) Colocalization of CK-20 (C) or CK-7 (F) with Mist1 (D and G, red) and DAPI (blue) in adult wild-type mice indicates that Mist1 is not expressed in intra- or interlobular ducts, respectively. Combining the staining patterns (E and H) reveals an exclusion of Mist1 from duct cell nuclei (arrows).
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fig1: Mist1 is expressed specifically in acinar cells during pancreatic development. (A) Immunohistochemistry using a Mist1-specific antibody reveals nuclear expression in putative acinar cells surrounding duct tissue (arrows) at E14.5. (B) By postnatal day 1 (PN1), Mist1 expression is wide spread in the pancreas, remaining exclusively in acinar cells. (C–H) Colocalization of CK-20 (C) or CK-7 (F) with Mist1 (D and G, red) and DAPI (blue) in adult wild-type mice indicates that Mist1 is not expressed in intra- or interlobular ducts, respectively. Combining the staining patterns (E and H) reveals an exclusion of Mist1 from duct cell nuclei (arrows).

Mentions: In adult tissue the Mist1 gene is transcribed exclusively in serous exocrine cells with high levels of expression, specifically in the acinar cells of the pancreas (Pin et al., 2000). Immunohistochemistry on staged embryos reveals that Mist1 protein is first detected in the nuclei of cells adjacent to pancreatic ducts as early as E13.0 (unpublished data). By E14.5, pancreatic ducts are surrounded by Mist1-positive cells that predominate eventually in the developing pancreatic tissue (Fig. 1 A). At birth (PN1) acini are clearly visible and all acinar cells are Mist1 positive (Fig. 1 B). The acinar-specific expression of Mist1 is maintained in adult pancreatic tissue as well. Dual fluorescence for cytokeratin (CK)-20 or CK-7 and Mist1 (Fig. 1, C–H) confirms that nuclear Mist1 is expressed only in acinar cells. There is a complete absence of Mist1 expression in intra- or interlobular pancreatic ducts and in all islet cells (see Fig. 3 A) in adult tissue.


The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity.

Pin CL, Rukstalis JM, Johnson C, Konieczny SF - J. Cell Biol. (2001)

Mist1 is expressed specifically in acinar cells during pancreatic development. (A) Immunohistochemistry using a Mist1-specific antibody reveals nuclear expression in putative acinar cells surrounding duct tissue (arrows) at E14.5. (B) By postnatal day 1 (PN1), Mist1 expression is wide spread in the pancreas, remaining exclusively in acinar cells. (C–H) Colocalization of CK-20 (C) or CK-7 (F) with Mist1 (D and G, red) and DAPI (blue) in adult wild-type mice indicates that Mist1 is not expressed in intra- or interlobular ducts, respectively. Combining the staining patterns (E and H) reveals an exclusion of Mist1 from duct cell nuclei (arrows).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198859&req=5

fig1: Mist1 is expressed specifically in acinar cells during pancreatic development. (A) Immunohistochemistry using a Mist1-specific antibody reveals nuclear expression in putative acinar cells surrounding duct tissue (arrows) at E14.5. (B) By postnatal day 1 (PN1), Mist1 expression is wide spread in the pancreas, remaining exclusively in acinar cells. (C–H) Colocalization of CK-20 (C) or CK-7 (F) with Mist1 (D and G, red) and DAPI (blue) in adult wild-type mice indicates that Mist1 is not expressed in intra- or interlobular ducts, respectively. Combining the staining patterns (E and H) reveals an exclusion of Mist1 from duct cell nuclei (arrows).
Mentions: In adult tissue the Mist1 gene is transcribed exclusively in serous exocrine cells with high levels of expression, specifically in the acinar cells of the pancreas (Pin et al., 2000). Immunohistochemistry on staged embryos reveals that Mist1 protein is first detected in the nuclei of cells adjacent to pancreatic ducts as early as E13.0 (unpublished data). By E14.5, pancreatic ducts are surrounded by Mist1-positive cells that predominate eventually in the developing pancreatic tissue (Fig. 1 A). At birth (PN1) acini are clearly visible and all acinar cells are Mist1 positive (Fig. 1 B). The acinar-specific expression of Mist1 is maintained in adult pancreatic tissue as well. Dual fluorescence for cytokeratin (CK)-20 or CK-7 and Mist1 (Fig. 1, C–H) confirms that nuclear Mist1 is expressed only in acinar cells. There is a complete absence of Mist1 expression in intra- or interlobular pancreatic ducts and in all islet cells (see Fig. 3 A) in adult tissue.

Bottom Line: 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.The exocrine disorganization is accompanied by increases in p8, RegI/PSP, and PAP1/RegIII gene expression, mimicking the molecular changes observed in pancreatic injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Child Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada.

ABSTRACT
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- (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.

Show MeSH
Related in: MedlinePlus