β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!
Liver-specific β-catenin knockout (β-Catenin-LKO) mice have revealed an essential role of β-catenin in metabolic zonation where it regulates pericentral gene expression and in initiating liver regeneration (LR) after partial hepatectomy (PH), by regulating expression of Cyclin-D1. However, what regulates β-catenin activity in these events remains an enigma. Here we investigate to what extent β-catenin activation is Wnt-signaling-dependent and the potential cell source of Wnts. We studied liver-specific Lrp5/6 KO (Lrp-LKO) mice where Wnt-signaling was abolished in hepatocytes while the β-catenin gene remained intact. Intriguingly, like β-catenin-LKO mice, Lrp-LKO exhibited a defect in metabolic zonation observed as a lack of glutamine synthetase (GS), Cyp1a2, and Cyp2e1. Lrp-LKO also displayed a significant delay in initiation of LR due to the absence of β-catenin-TCF4 association and lack of Cyclin-D1. To address the source of Wnt proteins in liver, we investigated conditional Wntless (Wls) KO mice, which lacked the ability to secrete Wnts from either liver epithelial cells (Wls-LKO), or macrophages including Kupffer cells (Wls-MKO), or endothelial cells (Wls-EKO). While Wls-EKO was embryonic lethal precluding further analysis in adult hepatic homeostasis and growth, Wls-LKO and Wls-MKO were viable but did not show any defect in hepatic zonation. Wls-LKO showed normal initiation of LR; however, Wls-MKO showed a significant but temporal deficit in LR that was associated with decreased β-catenin-TCF4 association and diminished Cyclin-D1 expression.


CONCLUSIONS
Wnt-signaling is the major upstream effector of β-catenin activity in pericentral hepatocytes and during LR. Hepatocytes, cholangiocytes, or macrophages are not the source of Wnts in regulating hepatic zonation. However, Kupffer cells are a major contributing source of Wnt secretion necessary for β-catenin activation during LR.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Jing
J
Yang
Laura E
LE
Mowry
Kari Nichole
KN
Nejak-Bowen
Hirohisa
H
Okabe
Cassandra R
CR
Diegel
Richard A
RA
Lang
Bart O
BO
Williams
Satdarshan P
SP
Monga
D022005:Adherens Junctions / Q000502:physiology; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006498:Hepatectomy; D007728:Kupffer Cells / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D051153:Wnt Proteins; D051176:beta Catenin