Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism.
OBJECTIVE
The Wnt pathway has previously been shown to play a role in hepatic zonation. Herein, we have explored the role of 3 key components (Apc, beta-catenin, and c-Myc) of the Wnt pathway in the zonation of ammonia metabolizing enzymes.


METHODS
Conditional deletion of Apc, beta-catenin, and c-Myc was induced in the livers of mice and the expression of periportal and perivenous hepatocyte markers was determined by polymerase chain reaction, Western blotting, and immunohistochemical techniques.


RESULTS
Under normal circumstances, the urea cycle enzyme carbamoylphosphate synthetase I (CPS I) is present in the periportal, intermediate, and the first few layers of the perivenous zone. In contrast, glutamine synthetase (GS)--and nuclear beta-catenin--is expressed in a complementary fashion in the last 1-2 cell layers of the perivenous zone. Conditional loss of Apc resulted in the expression of nuclear beta-catenin and GS in most hepatocytes irrespective of zone. Induction of GS in hepatocytes outside the normal perivenous zone was accompanied by a reduction in the expression of CPS I. Deletion of beta-catenin induces a loss of GS and a complementary increase in expression of CPS I irrespective of whether Apc is present. Remarkably, deletion of c-Myc did not perturb the pattern of zonation.


CONCLUSIONS
It has been shown that the Wnt pathway is key to imposing the pattern of zonation within the liver. Herein we have addressed the relevance of 3 major Wnt pathway components and show critically that the zonation is c-Myc independent but beta-catenin dependent.
Burke
Zoé D
ZD
Centre for Regenerative Medicine, Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, UK.
Reed
Karen R
KR
Phesse
Toby J
TJ
Sansom
Owen J
OJ
Clarke
Alan R
AR
Tosh
David
D
D000818:Animals; D002478:Cells, Cultured; D017353:Gene Deletion; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D051176:beta Catenin