Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development.
The mammalian small GTPase ADP-ribosylation factor 6 (ARF6) plays important roles in a wide variety of cellular events, including endocytosis, actin cytoskeletal reorganization, and phosphoinositide metabolism. However, physiological functions for ARF6 have not previously been examined. Here, we described the consequence of ARF6 ablation in mice, which manifests most obviously in the context of liver development. Livers from ARF6-/- embryos are smaller and exhibit hypocellularity, due to the onset of midgestational liver cell apoptosis. Preceding the apoptosis, however, defective hepatic cord formation is observed; the liver cells migrate abnormally upon exiting the primordial hepatic epithelial sheet and clump rather than becoming dispersed. Consistent with this observation, the ability of hepatocyte growth factor/scatter factor (HGF) to induce hepatic cord-like structures from ARF6-/- fetal hepatocytes cultured in vitro in collagen gel matrix is impaired. Finally, we show that endogenous ARF6 in wild-type fetal hepatocytes is activated in response to HGF stimulation. These results provide evidence that ARF6 is an essential component in the signaling pathway coupling HGF signaling to hepatic cord formation.
Suzuki
Teruhiko
T
Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Ten-nohdai, Tsukuba-shi, Ibaraki 305-8575, Japan.
Kanai
Yoshiakira
Y
Hara
Takahiko
T
Sasaki
Junko
J
Sasaki
Takehiko
T
Kohara
Michinori
M
Maehama
Tomohiko
T
Taya
Choji
C
Shitara
Hiroshi
H
Yonekawa
Hiromichi
H
Frohman
Michael A
MA
Yokozeki
Takeaki
T
Kanaho
Yasunori
Y
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D005091:Exons / Q000235:genetics; D005782:Gels; D018390:Gene Targeting; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000002:abnormalities / Q000166:cytology / Q000196:embryology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*
D000089982:ADP-Ribosylation Factor 6; D005782:Gels; D017228:Hepatocyte Growth Factor; D003094:Collagen; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; D020559:Monomeric GTP-Binding Proteins