title: Disruption of the transcription factor recombination signal-binding protein-Jkappa (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice.
abstract: Liver sinusoid (LS) endothelial cells (LSECs) support hepatocytes in resting livers and proliferate during liver regeneration to revascularize regenerated liver parenchyma. We report that recombination signal-binding protein-Jkappa (RBP-J), the critical transcription factor mediating Notch signaling, regulates both resting and regenerating LSECs. Conditional deletion of RBP-J resulted in LSEC proliferation and a veno-occlusive disease-like phenotype in the liver, as manifested by liver congestion, deposition of fibrin-like materials in LSs, edema in the space of Disse, and increased apoptosis of hepatocytes. Regeneration of liver was remarkably impaired, with reduced LSEC proliferation and destroyed sinusoidal structure. LSEC degeneration was obvious in the regenerating liver of RBP-J-deficient mice, with some LSECs losing cytoplasm, and organelles protruding into the remnant plasma-membrane of LSs to hamper the microcirculation and intensify veno-occlusive disease during liver regeneration. Hepatocytes were also degenerative, as shown by dilated endoplasmic reticulum, decreased proliferation, and increased apoptosis during liver regeneration. Molecular analyses revealed that the dynamic expression of several related molecules-such as vascular endothelial growth factor, vascular endothelial growth factor receptors 1 and 2, interleukin-6, and hepatocyte growth factor-was disturbed.
  
  
  CONCLUSIONS
  Notch/RBP-J signaling may play dual roles in LSECs: in resting liver it represses proliferation, and in regenerating liver it supports proliferation and functional differentiation.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Wang
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Hou
authors.forename: Guo-Rui
authors.initials: GR
authors.lastname: Dou
authors.forename: Yao-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Xing-Bin
authors.initials: XB
authors.lastname: Hu
authors.forename: Fei
authors.initials: F
authors.lastname: He
authors.forename: Fan
authors.initials: F
authors.lastname: Feng
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zhang
authors.forename: Ying-Min
authors.initials: YM
authors.lastname: Liang
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Dou
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000187:drug effects / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D051880:Receptors, Notch / Q000502:physiology; D000072056:Transcription Factor HES-1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D011070:Poly I-C; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C489734:Hes1 protein, mouse; C497443:Hif1a protein, mouse; C497571:Rbpj protein, mouse