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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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Progressive loss of β-catenin is associated with increased acinar cell disorganization in Mist1KO mice. (A) Western blot analysis of protein samples from wild-type (+/+) and Mist1KO (−/−) mice reveals a gradual loss of β-catenin expression in Mist1KO acinar tissue. (B) The loss of β-catenin expression is observed in all Mist1KO mice at 12 m of age, whereas Mist1LacZ mice (+/−) exhibit normal levels of β-catenin. E-cadherin expression remains relatively normal in Mist1KOmice. (C–F) Loss of β-catenin is specific to the acinar tissue in Mist1KO mice. The exocrine tissue of Mist1- mice exhibits a complete absence of β-catenin protein (compare C with D), whereas the islets (I, insets) and duct cells (arrows) continue to express normal β-catenin levels. Similar analysis with a ZO-1–specific antibody (E and F) reveals that tight junctions are maintained in Mist1KO mice, albeit surrounding severely distended lumens (arrows).
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fig7: Progressive loss of β-catenin is associated with increased acinar cell disorganization in Mist1KO mice. (A) Western blot analysis of protein samples from wild-type (+/+) and Mist1KO (−/−) mice reveals a gradual loss of β-catenin expression in Mist1KO acinar tissue. (B) The loss of β-catenin expression is observed in all Mist1KO mice at 12 m of age, whereas Mist1LacZ mice (+/−) exhibit normal levels of β-catenin. E-cadherin expression remains relatively normal in Mist1KOmice. (C–F) Loss of β-catenin is specific to the acinar tissue in Mist1KO mice. The exocrine tissue of Mist1- mice exhibits a complete absence of β-catenin protein (compare C with D), whereas the islets (I, insets) and duct cells (arrows) continue to express normal β-catenin levels. Similar analysis with a ZO-1–specific antibody (E and F) reveals that tight junctions are maintained in Mist1KO mice, albeit surrounding severely distended lumens (arrows).

Mentions: To examine the underlying cause of acinar cell disorganization in Mist1KO mice, proteins involved in adherens junction formation were analyzed. The adherens junction complex has been implicated as an important mediator of cellular polarity through maintaining cell–cell interactions and stabilizing the cytoskeleton (Petzelbauer et al., 2000). At 1 m of age, Mist1KO animals contain normal levels of β-catenin expression (Fig. 7 A). However, 5-m-old Mist1KO mice show a significant decrease in expression, and by 12 m of age β-catenin is diminished greatly. This gradual loss of expression is also observed for γ- and α-catenin (unpublished data) but not for E-cadherin (Fig. 7 B), suggesting that the catenin protein family is influenced specifically by the absence of Mist1. These results were further confirmed by immunohistochemical analysis on 12-m-old tissue in which β-catenin is not observed in acinar cells, although islet and ductal cells maintain appropriate levels and localization of the protein (Fig. 7, C–D). Analysis of the tight junction protein ZO-1 shows that it is maintained at appropriate levels with the protein localizing to presumptive apical borders of acinar cells (Fig. 7, E and F). However, the ZO-1 staining also reveals the expanded ducts that are characteristic of Mist1KO pancreatic tissue, delineating the border of distended lumens in the center of acinar cell clusters. Although tight junctions continue to form, the loss of catenin expression may account for the increasing severity of the Mist1KO phenotype and the eventual loss of the acinar cell phenotype.


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)

Progressive loss of β-catenin is associated with increased acinar cell disorganization in Mist1KO mice. (A) Western blot analysis of protein samples from wild-type (+/+) and Mist1KO (−/−) mice reveals a gradual loss of β-catenin expression in Mist1KO acinar tissue. (B) The loss of β-catenin expression is observed in all Mist1KO mice at 12 m of age, whereas Mist1LacZ mice (+/−) exhibit normal levels of β-catenin. E-cadherin expression remains relatively normal in Mist1KOmice. (C–F) Loss of β-catenin is specific to the acinar tissue in Mist1KO mice. The exocrine tissue of Mist1- mice exhibits a complete absence of β-catenin protein (compare C with D), whereas the islets (I, insets) and duct cells (arrows) continue to express normal β-catenin levels. Similar analysis with a ZO-1–specific antibody (E and F) reveals that tight junctions are maintained in Mist1KO mice, albeit surrounding severely distended lumens (arrows).
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Related In: Results  -  Collection

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fig7: Progressive loss of β-catenin is associated with increased acinar cell disorganization in Mist1KO mice. (A) Western blot analysis of protein samples from wild-type (+/+) and Mist1KO (−/−) mice reveals a gradual loss of β-catenin expression in Mist1KO acinar tissue. (B) The loss of β-catenin expression is observed in all Mist1KO mice at 12 m of age, whereas Mist1LacZ mice (+/−) exhibit normal levels of β-catenin. E-cadherin expression remains relatively normal in Mist1KOmice. (C–F) Loss of β-catenin is specific to the acinar tissue in Mist1KO mice. The exocrine tissue of Mist1- mice exhibits a complete absence of β-catenin protein (compare C with D), whereas the islets (I, insets) and duct cells (arrows) continue to express normal β-catenin levels. Similar analysis with a ZO-1–specific antibody (E and F) reveals that tight junctions are maintained in Mist1KO mice, albeit surrounding severely distended lumens (arrows).
Mentions: To examine the underlying cause of acinar cell disorganization in Mist1KO mice, proteins involved in adherens junction formation were analyzed. The adherens junction complex has been implicated as an important mediator of cellular polarity through maintaining cell–cell interactions and stabilizing the cytoskeleton (Petzelbauer et al., 2000). At 1 m of age, Mist1KO animals contain normal levels of β-catenin expression (Fig. 7 A). However, 5-m-old Mist1KO mice show a significant decrease in expression, and by 12 m of age β-catenin is diminished greatly. This gradual loss of expression is also observed for γ- and α-catenin (unpublished data) but not for E-cadherin (Fig. 7 B), suggesting that the catenin protein family is influenced specifically by the absence of Mist1. These results were further confirmed by immunohistochemical analysis on 12-m-old tissue in which β-catenin is not observed in acinar cells, although islet and ductal cells maintain appropriate levels and localization of the protein (Fig. 7, C–D). Analysis of the tight junction protein ZO-1 shows that it is maintained at appropriate levels with the protein localizing to presumptive apical borders of acinar cells (Fig. 7, E and F). However, the ZO-1 staining also reveals the expanded ducts that are characteristic of Mist1KO pancreatic tissue, delineating the border of distended lumens in the center of acinar cell clusters. Although tight junctions continue to form, the loss of catenin expression may account for the increasing severity of the Mist1KO phenotype and the eventual loss of the acinar cell phenotype.

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