Phenotype and growth behavior of residual β-catenin-positive hepatocytes in livers of β-catenin-deficient mice.
Signaling through the Wnt/β-catenin pathway is a crucial determinant of hepatic zonal gene expression, liver development, regeneration, and tumorigenesis. Transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) have proven their usefulness in elucidating these processes. We now found that a small number of hepatocytes escape the Cre-mediated gene knockout in that mouse model. The remaining β-catenin-positive hepatocytes showed approximately 25% higher cell volumes compared to the β-catenin-negative cells and exhibited a marker protein expression profile similar to that of normal perivenous hepatocytes or hepatoma cells with mutationally activated β-catenin. Surprisingly, the expression pattern was observed independent of the cell's position within the liver lobule, suggesting a malfunction of physiological periportal repression of perivenously expressed genes in β-catenin-deficient liver. Clusters of β-catenin-expressing hepatocytes lacked expression of the gap junction proteins Connexin 26 and 32. Nonetheless, β-catenin-positive hepatocytes had no striking proliferative advantage, but started to grow out on treatment with phenobarbital, a tumor-promoting agent known to facilitate the formation of mouse liver adenoma with activating mutations of Ctnnb1. Progressive re-population of Ctnnb1 knockout livers with wild-type hepatocytes was seen in aged mice with a pre-cirrhotic phenotype. In these large clusters of β-catenin-expressing hepatocytes, perivenous-specific gene expression was re-established. In summary, our data demonstrate that the zone-specificity of a hepatocyte's gene expression profile is dependent on the presence of β-catenin, and that β-catenin provides a proliferative advantage to hepatocytes when promoted with phenobarbital, or in a pre-cirrhotic environment.
Braeuning
Albert
A
Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany.
Singh
Yasmin
Y
Rignall
Benjamin
B
Buchmann
Albrecht
A
Hammad
Seddik
S
Othman
Amnah
A
von Recklinghausen
Iris
I
Godoy
Patricio
P
Hoehme
Stefan
S
Drasdo
Dirk
D
Hengstler
Jan G
JG
Schwarz
Michael
M
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002469:Cell Separation; D048429:Cell Size; D017630:Connexins / Q000172:deficiency; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010634:Phenobarbital / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D017630:Connexins; D012333:RNA, Messenger; D051176:beta Catenin; D019392:Cytochrome P-450 CYP2E1; D005974:Glutamate-Ammonia Ligase; D010634:Phenobarbital