Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development.
Beta-catenin, the central component of the canonical Wnt pathway, plays important roles in the processes of liver regeneration, growth, and cancer. Previously, we identified temporal expression of beta-catenin during liver development. Here, we characterize the hepatic phenotype, resulting from the successful deletion of beta-catenin in the developing hepatoblasts utilizing Foxa3-cyclization recombination and floxed-beta-catenin (exons 2 through 6) transgenic mice. Beta-catenin loss in developing livers resulted in significantly underdeveloped livers after embryonic day 12 (E12) with lethality occurring at around E17 stages. Histology revealed an overall deficient hepatocyte compartment due to (1) increased cell death due to oxidative stress and apoptosis, and (2) diminished expansion secondary to decreased cyclin-D1 and impaired proliferation. Also, the remnant hepatocytes demonstrated an immature phenotype as indicated by high nuclear to cytoplasmic ratio, poor cell polarity, absent glycogen, and decreased expression of key liver-enriched transcription factors: CCAAT-enhancer binding protein-alpha and hepatocyte nuclear factor-4alpha. A paucity of primitive bile ducts was also observed. While the stem cell assays demonstrated no intrinsic defect in hematopoiesis, distorted hepatic architecture and deficient hepatocyte compartments resulted in defective endothelial cell organization leading to overall fetal pallor.


CONCLUSIONS
Beta-catenin regulates multiple, critical events during the process of hepatic morphogenesis, including hepatoblast maturation, expansion, and survival, making it indispensable to survival.
Tan
Xinping
X
Department of Pathology, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
Yuan
Youzhong
Y
Zeng
Gang
G
Apte
Udayan
U
Thompson
Michael D
MD
Cieply
Benjamin
B
Stolz
Donna B
DB
Michalopoulos
George K
GK
Kaestner
Klaus H
KH
Monga
Satdarshan P S
SP
D000818:Animals; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics; D051176:beta Catenin / Q000172:deficiency* / Q000235:genetics*
D012709:Serum Albumin; D000509:alpha-Fetoproteins; D051176:beta Catenin; D012313:RNA