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Molecular and Cellular Biology, August 2006, p. 6149-6156, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00298-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Crucial Role of the Small GTPase ARF6 in Hepatic Cord Formation during Liver Development

Teruhiko Suzuki,1,2 Yoshiakira Kanai,3 Takahiko Hara,4 Junko Sasaki,8 Takehiko Sasaki,8 Michinori Kohara,5 Tomohiko Maehama,6 Choji Taya,7 Hiroshi Shitara,7 Hiromichi Yonekawa,7 Michael A. Frohman,9 Takeaki Yokozeki,1 and Yasunori Kanaho1*

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 305-8575, Japan,1 Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongoh, Bunkyo-ku, Tokyo 113-0033, Japan,2 Department of Veterinary Anatomy, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1 Yayoi Bunkyo-ku, Tokyo 113-8657, Japan,3 Stem Cell Project,4 Infectious Diseases Project,5 Biomembrane Signalling Project,6 Core Technology & Research Center, Laboratory of Mouse Model for Human Heritable Diseases, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan,7 Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan,8 Center for Developmental Genetics and Department of Pharmacology, Stony Brook University, New York, New York 11794-51409

Received 17 February 2006/ Returned for modification 28 March 2006/ Accepted 3 June 2006

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.

* Corresponding author. Mailing address: 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. Phone: 81-29-853-3282. Fax: 29-853-3271. E-mail: ykanaho{at}md.tsukuba.ac.jp.

Molecular and Cellular Biology, August 2006, p. 6149-6156, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00298-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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