Disruption of the transcription factor recombination signal-binding protein-Jkappa (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice.
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.
Wang
Lin
L
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
Wang
Chun-Mei
CM
Hou
Li-Hong
LH
Dou
Guo-Rui
GR
Wang
Yao-Chun
YC
Hu
Xing-Bin
XB
He
Fei
F
Feng
Fan
F
Zhang
Hong-Wei
HW
Liang
Ying-Min
YM
Dou
Ke-Feng
KF
Han
Hua
H
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
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