GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:25446530

From GONUTS
Jump to: navigation, search
Citation

Falix, FA, Weeda, VB, Labruyere, WT, Poncy, A, de Waart, DR, Hakvoort, TB, Lemaigre, F, Gaemers, IC, Aronson, DC and Lamers, WH (2014) Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. Dev. Biol. 396:201-13

Abstract

Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1β, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation.

Links

PubMed Online version:10.1016/j.ydbio.2014.10.002

Keywords

Analysis of Variance; Animals; Bile Ducts/abnormalities; Bile Ducts/growth & development; DNA Primers/genetics; Hepatocyte Nuclear Factor 6/metabolism; Histological Techniques; Immunohistochemistry; Liver/metabolism; Mice; Mice, Knockout; Organogenesis/genetics; Organogenesis/physiology; Polymerase Chain Reaction; Receptor, Notch2/deficiency; Regression Analysis; Weaning

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HNF6

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPYA

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:0001889: liver development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:0072576: liver morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:0072574: hepatocyte proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:0035622: intrahepatic bile duct development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:NOTC2

acts_upstream_of_or_within

GO:1990705: cholangiocyte proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3617328

P

Seeded From UniProt

complete

MOUSE:AATC

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HNF1B

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXA1

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HHEX

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ANXA4

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX9

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H4

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR0B2

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TGFR2

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RS19

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:JAG1

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:K1C19

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXA2

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TGFB1

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CEBPA

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KI67

acts_upstream_of_or_within

GO:0072574: hepatocyte proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KI67

acts_upstream_of_or_within

GO:1990705: cholangiocyte proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.