Phenotype and growth behavior of residual ß-catenin-positive hepatocytes in livers of ß-catenin-deficient mice.
Histochem Cell Biol
; 134(5): 469-81, 2010 Nov.
Article
en En
| MEDLINE
| ID: mdl-20886225
ABSTRACT
Signaling through the Wnt/ß-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 ß-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 ß-catenin-positive hepatocytes showed approximately 25% higher cell volumes compared to the ß-catenin-negative cells and exhibited a marker protein expression profile similar to that of normal perivenous hepatocytes or hepatoma cells with mutationally activated ß-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 ß-catenin-deficient liver. Clusters of ß-catenin-expressing hepatocytes lacked expression of the gap junction proteins Connexin 26 and 32. Nonetheless, ß-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 ß-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 ß-catenin, and that ß-catenin provides a proliferative advantage to hepatocytes when promoted with phenobarbital, or in a pre-cirrhotic environment.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hepatocitos
/
Beta Catenina
Límite:
Animals
Idioma:
En
Revista:
Histochem Cell Biol
Asunto de la revista:
CITOLOGIA
/
HISTOCITOQUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Alemania