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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: 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.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.

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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Lesions within Mist1KO pancreatic tissue contain cells that coexpress the Mist1 locus and duct cell markers. (A and B) Immunohistochemistry with CK-20–specific antibodies reveals the normal accumulation of duct tissue within wild-type animals (A). In contrast, the Mist1KO pancreas contains large accumulations of duct cells throughout the exocrine tissue (B, open arrow). Identical staining patterns are obtained with antibodies against CK-7 (unpublished data). Insets reveal normal insulin-positive islets in these animals. (C–E) Staining for CK-20 and β-gal reveals apparent coexpression of acinar- and duct-specific markers in the same cells. The filled and open arrows point to β-gal–positive and –negative nuclei, respectively, within CK-20–positive cells. (F–H) Immunohistochemistry for SMA on wild-type (F) and  (G) tissue sections. SMA expression is limited to blood vessels in the wild-type mouse. However, several SMA-positive cells are observed throughout the  tissue with one particular lesion shown (H). Higher magnification (inset, costained with DAPI) indicates that these cells likely represent small blood vessels (filled arrow) and stellate cells (open arrow). Staining of  sections with Gomori's trichrome (H) also reveals the vast accumulating connective tissue (green, arrows) found in many fibrotic lesions.
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fig5: Lesions within Mist1KO pancreatic tissue contain cells that coexpress the Mist1 locus and duct cell markers. (A and B) Immunohistochemistry with CK-20–specific antibodies reveals the normal accumulation of duct tissue within wild-type animals (A). In contrast, the Mist1KO pancreas contains large accumulations of duct cells throughout the exocrine tissue (B, open arrow). Identical staining patterns are obtained with antibodies against CK-7 (unpublished data). Insets reveal normal insulin-positive islets in these animals. (C–E) Staining for CK-20 and β-gal reveals apparent coexpression of acinar- and duct-specific markers in the same cells. The filled and open arrows point to β-gal–positive and –negative nuclei, respectively, within CK-20–positive cells. (F–H) Immunohistochemistry for SMA on wild-type (F) and (G) tissue sections. SMA expression is limited to blood vessels in the wild-type mouse. However, several SMA-positive cells are observed throughout the tissue with one particular lesion shown (H). Higher magnification (inset, costained with DAPI) indicates that these cells likely represent small blood vessels (filled arrow) and stellate cells (open arrow). Staining of sections with Gomori's trichrome (H) also reveals the vast accumulating connective tissue (green, arrows) found in many fibrotic lesions.

Mentions: Analysis of Mist1KO pancreatic tissue with antibodies specific to CK-20 (Fig. 5, A and B) and CK-7 (unpublished data) confirms that these mice develop extensive duct cell accumulations throughout the tissue. CK staining is accompanied by a decrease in CPA (unpublished data) and amylase expression (Fig. 6). Many cells coexpress β-gal and CK-20 (Fig. 5, C–E), suggesting the possibility that acinar cells may be reverting to a duct cell phenotype. Mist1KO pancreatic tissue also exhibits a significant increase in the number of desmin- and vimentin-positive cells (unpublished data) and the appearance of cells expressing smooth muscle actin (SMA) (Fig. 5 G). Many of the SMA-positive cells exist within the walls of small blood vessels and reveal an increased vascularity of the Mist1KO pancreatic tissue. However, there also are many single cells that are not part of the vascularity. The expression of SMA in these cells suggests that they are activated stellate cells, which promote increased collagen deposition and are characteristic of several pancreatic diseases (Haber et al., 1999). Gomori's trichrome staining confirms an increase in connective tissue (Fig. 5 H), indicating that fibrosis is also occurring in the exocrine pancreas of these animals. The presence of activated stellate cells with increased ductal organization suggests that Mist1KO acinar tissue exhibits significant pancreatic injury.


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)

Lesions within Mist1KO pancreatic tissue contain cells that coexpress the Mist1 locus and duct cell markers. (A and B) Immunohistochemistry with CK-20–specific antibodies reveals the normal accumulation of duct tissue within wild-type animals (A). In contrast, the Mist1KO pancreas contains large accumulations of duct cells throughout the exocrine tissue (B, open arrow). Identical staining patterns are obtained with antibodies against CK-7 (unpublished data). Insets reveal normal insulin-positive islets in these animals. (C–E) Staining for CK-20 and β-gal reveals apparent coexpression of acinar- and duct-specific markers in the same cells. The filled and open arrows point to β-gal–positive and –negative nuclei, respectively, within CK-20–positive cells. (F–H) Immunohistochemistry for SMA on wild-type (F) and  (G) tissue sections. SMA expression is limited to blood vessels in the wild-type mouse. However, several SMA-positive cells are observed throughout the  tissue with one particular lesion shown (H). Higher magnification (inset, costained with DAPI) indicates that these cells likely represent small blood vessels (filled arrow) and stellate cells (open arrow). Staining of  sections with Gomori's trichrome (H) also reveals the vast accumulating connective tissue (green, arrows) found in many fibrotic lesions.
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Related In: Results  -  Collection

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fig5: Lesions within Mist1KO pancreatic tissue contain cells that coexpress the Mist1 locus and duct cell markers. (A and B) Immunohistochemistry with CK-20–specific antibodies reveals the normal accumulation of duct tissue within wild-type animals (A). In contrast, the Mist1KO pancreas contains large accumulations of duct cells throughout the exocrine tissue (B, open arrow). Identical staining patterns are obtained with antibodies against CK-7 (unpublished data). Insets reveal normal insulin-positive islets in these animals. (C–E) Staining for CK-20 and β-gal reveals apparent coexpression of acinar- and duct-specific markers in the same cells. The filled and open arrows point to β-gal–positive and –negative nuclei, respectively, within CK-20–positive cells. (F–H) Immunohistochemistry for SMA on wild-type (F) and (G) tissue sections. SMA expression is limited to blood vessels in the wild-type mouse. However, several SMA-positive cells are observed throughout the tissue with one particular lesion shown (H). Higher magnification (inset, costained with DAPI) indicates that these cells likely represent small blood vessels (filled arrow) and stellate cells (open arrow). Staining of sections with Gomori's trichrome (H) also reveals the vast accumulating connective tissue (green, arrows) found in many fibrotic lesions.
Mentions: Analysis of Mist1KO pancreatic tissue with antibodies specific to CK-20 (Fig. 5, A and B) and CK-7 (unpublished data) confirms that these mice develop extensive duct cell accumulations throughout the tissue. CK staining is accompanied by a decrease in CPA (unpublished data) and amylase expression (Fig. 6). Many cells coexpress β-gal and CK-20 (Fig. 5, C–E), suggesting the possibility that acinar cells may be reverting to a duct cell phenotype. Mist1KO pancreatic tissue also exhibits a significant increase in the number of desmin- and vimentin-positive cells (unpublished data) and the appearance of cells expressing smooth muscle actin (SMA) (Fig. 5 G). Many of the SMA-positive cells exist within the walls of small blood vessels and reveal an increased vascularity of the Mist1KO pancreatic tissue. However, there also are many single cells that are not part of the vascularity. The expression of SMA in these cells suggests that they are activated stellate cells, which promote increased collagen deposition and are characteristic of several pancreatic diseases (Haber et al., 1999). Gomori's trichrome staining confirms an increase in connective tissue (Fig. 5 H), indicating that fibrosis is also occurring in the exocrine pancreas of these animals. The presence of activated stellate cells with increased ductal organization suggests that Mist1KO acinar tissue exhibits significant pancreatic injury.

Bottom Line: 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.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.

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