beta-Catenin is critical for early postnatal liver growth.
The Wnt/beta-catenin pathway plays an important role in embryonic liver development, morphogenesis, and organogenesis. Here, we report on the activation of beta-catenin during early postnatal liver growth. Modulation of beta-catenin expression was studied in CD-1 mice livers over a time course of 0 to 30 postnatal days (PD) and 3 mo. Increases in total and active beta-catenin were observed in developing livers from PD 5 to 20. A concomitant increase in the beta-catenin-transcription factor (TCF) complex along with nuclear and cytoplasmic beta-catenin was also evident, which coincided with ongoing hepatocyte proliferation by PCNA immunohistochemistry. This activation of beta-catenin was multifactorial, including cyclical inhibition of glycogen synthase kinase-3beta, suppression of casein kinase-IIalpha, and a transient increase in beta-catenin gene expression. Coprecipitation experiments revealed the formation of the beta-catenin-cadherin complex at PD 5, whereas adequate beta-catenin-c-Met complex at the hepatocyte membrane did not form until PD 20, which might be contributing to the free beta-catenin pool during early postnatal growth. Furthermore, beta-catenin liver-specific knockout mice exhibited smaller livers at PD 30, secondary to diminished hepatocyte proliferation. These data indicate that the activation of beta-catenin is critical for early postnatal liver growth and development.
Apte
Udayan
U
Depts. of Pathology and Medicine, Univ. of Pittsburgh School of Medicine, 200 Lothrop St., S-421 BST, Pittsburgh, PA 15216, USA.
Zeng
Gang
G
Thompson
Michael D
MD
Muller
Peggy
P
Micsenyi
Amanda
A
Cieply
Benjamin
B
Kaestner
Klaus H
KH
Monga
Satdarshan P S
SP
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051820:TCF Transcription Factors / Q000378:metabolism; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D015820:Cadherins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D019859:Proto-Oncogene Proteins c-met; D047390:Casein Kinase II; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3