Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration.
The Notch/Jagged signaling pathway is important for cellular differentiation and proliferation. Its dysfunction is associated with human pathologies in several tissues including liver. Point mutations in Jagged-1 gene are the cause for Alagille syndrome, associated with paucity of intrahepatic bile ducts. To determine the putative role of the trans-membrane receptor Notch and its ligand Jagged-1 in liver regeneration, we investigated the expression of Notch and Jagged-1 in rat liver following 2/3 partial hepatectomy. Immunohistochemical staining of normal rat liver showed that Notch was expressed in hepatocytes, bile duct cells and endothelial cells, whereas Jagged-1 was expressed in bile duct cells and hepatocytes. Both Notch-1 and Jagged-1 proteins were upregulated in hepatocytes after partial hepatectomy up to day 4. After partial hepatectomy, nuclear translocation of the intracellular cytoplasmic domain of Notch (NICD) increased and peaked within 15 minutes, indicating the activation of Notch. Expression of the Notch-dependent target gene (HES-1) expression increased within 30-60 minutes. Addition of recombinant Jagged-1 protein to primary cultures of hepatocytes stimulated hepatocyte DNA synthesis. Furthermore, injection of silencing RNA for Notch and Jagged-1 to livers 2 days before partial hepatectomy significantly suppressed proliferation of hepatocytes at days 2 to 4 of the regenerative response. In conclusion, Notch/Jagged signaling pathway is activated during liver regeneration and is potentially contributing to signals affecting cell growth and differentiation.
Köhler
Christoph
C
Department of Internal Medicine, University of Halle, Halle, Germany.
Bell
Aaron W
AW
Bowen
William C
WC
Monga
Satdarshan P
SP
Fleig
Wolfgang
W
Michalopoulos
George K
GK
D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002135:Calcium-Binding Proteins; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008565:Membrane Proteins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D015854:Up-Regulation
D000963:Antimetabolites; D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C489735:Hes1 protein, rat; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; C497763:Notch1 protein, rat