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Notch signaling regulates bile duct morphogenesis in mice.

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

Bottom Line: 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.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.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 embryonic bile duct morphogenesis in Jag1dDSL/+ Notch2del1/+ mice.Cytokeratin immunostaining of control littermate and Jag1dDSL/+ Notch2del1/+ liver sections at the indicated ages. A,B. At E16.5, both control (A) and Jag1dDSL/+ Notch2del1/+ (B) have formed a partly bilayered ductal plate (arrowheads). C–F. Over the next several days, focal dilations (arrowheads) form in the ductal plate of both control and mutant embryos. Other regions of the ductal plate begin to regress. G,H. At P7, the focal dilations have formed epithelial bile ducts incorporated into the portal mesenchyme (arrows) in the control liver (G), while the Jag1dDSL/+ Notch2del1/+ liver (H) exhibits only ductal plate remnants (arrowheads).
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pone-0001851-g001: Defects in embryonic bile duct morphogenesis in Jag1dDSL/+ Notch2del1/+ mice.Cytokeratin immunostaining of control littermate and Jag1dDSL/+ Notch2del1/+ liver sections at the indicated ages. A,B. At E16.5, both control (A) and Jag1dDSL/+ Notch2del1/+ (B) have formed a partly bilayered ductal plate (arrowheads). C–F. Over the next several days, focal dilations (arrowheads) form in the ductal plate of both control and mutant embryos. Other regions of the ductal plate begin to regress. G,H. At P7, the focal dilations have formed epithelial bile ducts incorporated into the portal mesenchyme (arrows) in the control liver (G), while the Jag1dDSL/+ Notch2del1/+ liver (H) exhibits only ductal plate remnants (arrowheads).

Mentions: Our previous study [15] analyzed late embryonic and postnatal livers, and did not establish whether bile duct paucity in mice doubly heterozygous for a Jag1 allele (Jag1dDSL) [16] and a Notch2 hypomorphic allele (Notch2del1) [19] was due to defects in differentiation of bile duct precursors from the bipotential hepatoblast, or whether it was due to defects in morphogenesis of the ductal plate. Therefore, we analyzed livers of Jag1dDSL/+ Notch2del1/+ double heterozygous mice by cytokeratin immunostaining from embryonic day (E) 16.5 through postnatal day (P) 7. At E16.5 in control littermate embryos, cytokeratin immunostaining revealed the presence of a partly bilayered ductal plate at the interface of the portal mesenchyme and the liver parenchyma (Fig. 1A). Over the next several days, the ductal plate remodels by a process in which focal dilations appear between the two cell layers of the plate (Fig. 1C,E). By P7, some of these focal dilations give rise to patent epithelial bile ducts incorporated into the portal mesenchyme (Fig. 1G), while the remainder of the ductal plate involutes. Cytokeratin immunostaining of liver sections from Jag1dDSL/+ Notch2del1/+ double heterozygous mice revealed that they were very similar to control littermate sections through at least P0. In the Jag1dDSL/+ Notch2del1/+ mice, a ductal plate formed (Fig. 1B) and focal dilations appeared (Fig. 1D,F). However, postnatal remodeling to form a patent epithelial bile duct did not occur. Instead, as we reported in our initial study [15], by P7 only ductal plate remnants remained in most portal tracts (Fig. 1H). These results indicate that in the Jag1/Notch2 double heterozygote mouse, bile duct paucity results from defects in bile duct morphogenesis, not from defects in differentiation of bile duct precursors from the bipotential hepatoblast.


Notch signaling regulates bile duct morphogenesis in mice.

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

Defects in embryonic bile duct morphogenesis in Jag1dDSL/+ Notch2del1/+ mice.Cytokeratin immunostaining of control littermate and Jag1dDSL/+ Notch2del1/+ liver sections at the indicated ages. A,B. At E16.5, both control (A) and Jag1dDSL/+ Notch2del1/+ (B) have formed a partly bilayered ductal plate (arrowheads). C–F. Over the next several days, focal dilations (arrowheads) form in the ductal plate of both control and mutant embryos. Other regions of the ductal plate begin to regress. G,H. At P7, the focal dilations have formed epithelial bile ducts incorporated into the portal mesenchyme (arrows) in the control liver (G), while the Jag1dDSL/+ Notch2del1/+ liver (H) exhibits only ductal plate remnants (arrowheads).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2266994&req=5

pone-0001851-g001: Defects in embryonic bile duct morphogenesis in Jag1dDSL/+ Notch2del1/+ mice.Cytokeratin immunostaining of control littermate and Jag1dDSL/+ Notch2del1/+ liver sections at the indicated ages. A,B. At E16.5, both control (A) and Jag1dDSL/+ Notch2del1/+ (B) have formed a partly bilayered ductal plate (arrowheads). C–F. Over the next several days, focal dilations (arrowheads) form in the ductal plate of both control and mutant embryos. Other regions of the ductal plate begin to regress. G,H. At P7, the focal dilations have formed epithelial bile ducts incorporated into the portal mesenchyme (arrows) in the control liver (G), while the Jag1dDSL/+ Notch2del1/+ liver (H) exhibits only ductal plate remnants (arrowheads).
Mentions: Our previous study [15] analyzed late embryonic and postnatal livers, and did not establish whether bile duct paucity in mice doubly heterozygous for a Jag1 allele (Jag1dDSL) [16] and a Notch2 hypomorphic allele (Notch2del1) [19] was due to defects in differentiation of bile duct precursors from the bipotential hepatoblast, or whether it was due to defects in morphogenesis of the ductal plate. Therefore, we analyzed livers of Jag1dDSL/+ Notch2del1/+ double heterozygous mice by cytokeratin immunostaining from embryonic day (E) 16.5 through postnatal day (P) 7. At E16.5 in control littermate embryos, cytokeratin immunostaining revealed the presence of a partly bilayered ductal plate at the interface of the portal mesenchyme and the liver parenchyma (Fig. 1A). Over the next several days, the ductal plate remodels by a process in which focal dilations appear between the two cell layers of the plate (Fig. 1C,E). By P7, some of these focal dilations give rise to patent epithelial bile ducts incorporated into the portal mesenchyme (Fig. 1G), while the remainder of the ductal plate involutes. Cytokeratin immunostaining of liver sections from Jag1dDSL/+ Notch2del1/+ double heterozygous mice revealed that they were very similar to control littermate sections through at least P0. In the Jag1dDSL/+ Notch2del1/+ mice, a ductal plate formed (Fig. 1B) and focal dilations appeared (Fig. 1D,F). However, postnatal remodeling to form a patent epithelial bile duct did not occur. Instead, as we reported in our initial study [15], by P7 only ductal plate remnants remained in most portal tracts (Fig. 1H). These results indicate that in the Jag1/Notch2 double heterozygote mouse, bile duct paucity results from defects in bile duct morphogenesis, not from defects in differentiation of bile duct precursors from the bipotential hepatoblast.

Bottom Line: 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.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.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