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Notch signaling regulates bile duct morphogenesis in mice.

Lozier J, McCright B, Gridley T - PLoS ONE (2008)

Bottom Line: Alagille syndrome is a developmental disorder caused predominantly by mutations in the Jagged1 (JAG1) gene, which encodes a ligand for Notch family receptors.However, our previous study did not establish whether bile duct paucity in Jag1/Notch2 double heterozygous mice resulted from impaired differentiation of bile duct precursor cells, or from defects in bile duct morphogenesis.Our data support a model in which bile duct paucity in Notch pathway loss of function mutant mice results from defects in bile duct morphogenesis rather than cell fate specification.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT

Background: Alagille syndrome is a developmental disorder caused predominantly by mutations in the Jagged1 (JAG1) gene, which encodes a ligand for Notch family receptors. A characteristic feature of Alagille syndrome is intrahepatic bile duct paucity. We described previously that mice doubly heterozygous for Jag1 and Notch2 mutations are an excellent model for Alagille syndrome. However, our previous study did not establish whether bile duct paucity in Jag1/Notch2 double heterozygous mice resulted from impaired differentiation of bile duct precursor cells, or from defects in bile duct morphogenesis.

Methodology/principal findings: Here we characterize embryonic biliary tract formation in our previously described Jag1/Notch2 double heterozygous Alagille syndrome model, and describe another mouse model of bile duct paucity resulting from liver-specific deletion of the Notch2 gene.

Conclusions/significance: Our data support a model in which bile duct paucity in Notch pathway loss of function mutant mice results from defects in bile duct morphogenesis rather than cell fate specification.

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Defects in bile duct formation in Notch2-cko mice using either the Notch2del2 or Notch2del3 alleles.A,B. Hematoxylin and eosin-stained sections at P7 of control littermate (CT) and Notch2-cko mice using the Notch2del2 allele. Bile ducts (arrow) are observed in the periportal region of the control littermate (A), but not the Notch2-cko mouse (B). C–F. DBA lectin staining. C,D. Control littermate and Notch2-cko mice using the Notch2del2 allele at P7. E,F. Control littermate and Notch2-cko mice using the Notch2del3 allele at P3. DBA-positive cells form patent bile ducts (arrows) adjacent to the portal veins in control mice (C,E). In Notch2-cko mice using either the Notch2del2 (D) or Notch2del3 (F) allele, small numbers of DBA-positive cells (arrowheads) are present adjacent to the portal veins, but these cells have not formed patent ducts. G,H. Cytokeratin immunostaining of control littermate and Notch2-cko mice (Notch2del2 allele) at P7. The ductal plate of the control liver (G) has remodeled into epithelial bile ducts (arrows), while the Notch2-cko liver (H) exhibits only ductal plate remnants (arrowheads).
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pone-0001851-g004: Defects in bile duct formation in Notch2-cko mice using either the Notch2del2 or Notch2del3 alleles.A,B. Hematoxylin and eosin-stained sections at P7 of control littermate (CT) and Notch2-cko mice using the Notch2del2 allele. Bile ducts (arrow) are observed in the periportal region of the control littermate (A), but not the Notch2-cko mouse (B). C–F. DBA lectin staining. C,D. Control littermate and Notch2-cko mice using the Notch2del2 allele at P7. E,F. Control littermate and Notch2-cko mice using the Notch2del3 allele at P3. DBA-positive cells form patent bile ducts (arrows) adjacent to the portal veins in control mice (C,E). In Notch2-cko mice using either the Notch2del2 (D) or Notch2del3 (F) allele, small numbers of DBA-positive cells (arrowheads) are present adjacent to the portal veins, but these cells have not formed patent ducts. G,H. Cytokeratin immunostaining of control littermate and Notch2-cko mice (Notch2del2 allele) at P7. The ductal plate of the control liver (G) has remodeled into epithelial bile ducts (arrows), while the Notch2-cko liver (H) exhibits only ductal plate remnants (arrowheads).

Mentions: The biliary tract defects exhibited by Notch2-cko mice were very similar to those exhibited by Jag1dDSL/+ Notch2del1/+ mice (compare Fig. 1 with Fig. 4). Examination of histological sections of the livers of Notch2-cko mice revealed that few morphologically identifiable bile ducts were present (Fig. 4B). Analysis of Dolichos biflorus agglutinin (DBA) lectin expression, a cholangiocyte marker [26], revealed that DBA-positive cells formed patent bile ducts adjacent to the portal veins in littermate control mice (Fig. 4C,E). In Notch2-cko mice, DBA-positive cells were present in small numbers adjacent to the portal veins, but these cells were not arranged into patent epithelial ducts (Fig. 4D,F). Biliary tract defects were similar using either the Notch2del2 (Fig. 4B,D) or Notch2del3 (Fig. 4F) allele in combination with the Notch2flox allele. Similarly to portal tracts of Jag1dDSL/+ Notch2del1/+ mice, cytokeratin immunostaining revealed that by P7 only ductal plate remnants were detected in most Notch2-cko portal tracts (Fig. 4H), while well-formed bile ducts incorporated into the portal mesenchyme were present in the littermate controls (Fig. 4G).


Notch signaling regulates bile duct morphogenesis in mice.

Lozier J, McCright B, Gridley T - PLoS ONE (2008)

Defects in bile duct formation in Notch2-cko mice using either the Notch2del2 or Notch2del3 alleles.A,B. Hematoxylin and eosin-stained sections at P7 of control littermate (CT) and Notch2-cko mice using the Notch2del2 allele. Bile ducts (arrow) are observed in the periportal region of the control littermate (A), but not the Notch2-cko mouse (B). C–F. DBA lectin staining. C,D. Control littermate and Notch2-cko mice using the Notch2del2 allele at P7. E,F. Control littermate and Notch2-cko mice using the Notch2del3 allele at P3. DBA-positive cells form patent bile ducts (arrows) adjacent to the portal veins in control mice (C,E). In Notch2-cko mice using either the Notch2del2 (D) or Notch2del3 (F) allele, small numbers of DBA-positive cells (arrowheads) are present adjacent to the portal veins, but these cells have not formed patent ducts. G,H. Cytokeratin immunostaining of control littermate and Notch2-cko mice (Notch2del2 allele) at P7. The ductal plate of the control liver (G) has remodeled into epithelial bile ducts (arrows), while the Notch2-cko liver (H) exhibits only ductal plate remnants (arrowheads).
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Related In: Results  -  Collection

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pone-0001851-g004: Defects in bile duct formation in Notch2-cko mice using either the Notch2del2 or Notch2del3 alleles.A,B. Hematoxylin and eosin-stained sections at P7 of control littermate (CT) and Notch2-cko mice using the Notch2del2 allele. Bile ducts (arrow) are observed in the periportal region of the control littermate (A), but not the Notch2-cko mouse (B). C–F. DBA lectin staining. C,D. Control littermate and Notch2-cko mice using the Notch2del2 allele at P7. E,F. Control littermate and Notch2-cko mice using the Notch2del3 allele at P3. DBA-positive cells form patent bile ducts (arrows) adjacent to the portal veins in control mice (C,E). In Notch2-cko mice using either the Notch2del2 (D) or Notch2del3 (F) allele, small numbers of DBA-positive cells (arrowheads) are present adjacent to the portal veins, but these cells have not formed patent ducts. G,H. Cytokeratin immunostaining of control littermate and Notch2-cko mice (Notch2del2 allele) at P7. The ductal plate of the control liver (G) has remodeled into epithelial bile ducts (arrows), while the Notch2-cko liver (H) exhibits only ductal plate remnants (arrowheads).
Mentions: The biliary tract defects exhibited by Notch2-cko mice were very similar to those exhibited by Jag1dDSL/+ Notch2del1/+ mice (compare Fig. 1 with Fig. 4). Examination of histological sections of the livers of Notch2-cko mice revealed that few morphologically identifiable bile ducts were present (Fig. 4B). Analysis of Dolichos biflorus agglutinin (DBA) lectin expression, a cholangiocyte marker [26], revealed that DBA-positive cells formed patent bile ducts adjacent to the portal veins in littermate control mice (Fig. 4C,E). In Notch2-cko mice, DBA-positive cells were present in small numbers adjacent to the portal veins, but these cells were not arranged into patent epithelial ducts (Fig. 4D,F). Biliary tract defects were similar using either the Notch2del2 (Fig. 4B,D) or Notch2del3 (Fig. 4F) allele in combination with the Notch2flox allele. Similarly to portal tracts of Jag1dDSL/+ Notch2del1/+ mice, cytokeratin immunostaining revealed that by P7 only ductal plate remnants were detected in most Notch2-cko portal tracts (Fig. 4H), while well-formed bile ducts incorporated into the portal mesenchyme were present in the littermate controls (Fig. 4G).

Bottom Line: Alagille syndrome is a developmental disorder caused predominantly by mutations in the Jagged1 (JAG1) gene, which encodes a ligand for Notch family receptors.However, our previous study did not establish whether bile duct paucity in Jag1/Notch2 double heterozygous mice resulted from impaired differentiation of bile duct precursor cells, or from defects in bile duct morphogenesis.Our data support a model in which bile duct paucity in Notch pathway loss of function mutant mice results from defects in bile duct morphogenesis rather than cell fate specification.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.

ABSTRACT

Background: Alagille syndrome is a developmental disorder caused predominantly by mutations in the Jagged1 (JAG1) gene, which encodes a ligand for Notch family receptors. A characteristic feature of Alagille syndrome is intrahepatic bile duct paucity. We described previously that mice doubly heterozygous for Jag1 and Notch2 mutations are an excellent model for Alagille syndrome. However, our previous study did not establish whether bile duct paucity in Jag1/Notch2 double heterozygous mice resulted from impaired differentiation of bile duct precursor cells, or from defects in bile duct morphogenesis.

Methodology/principal findings: Here we characterize embryonic biliary tract formation in our previously described Jag1/Notch2 double heterozygous Alagille syndrome model, and describe another mouse model of bile duct paucity resulting from liver-specific deletion of the Notch2 gene.

Conclusions/significance: Our data support a model in which bile duct paucity in Notch pathway loss of function mutant mice results from defects in bile duct morphogenesis rather than cell fate specification.

Show MeSH
Related in: MedlinePlus