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First published online 20 March 2008
doi: 10.1242/dev.016634

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Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19^ARF expression

Atsushi Suzuki^1,2,*, Sayaka Sekiya¹, Dirk Büscher^3,, Juan Carlos Izpisúa Belmonte^3,4 and Hideki Taniguchi^2,5

¹ Division of Organogenesis and Regeneration, Post-Genome Science Center, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
² Research Unit for Organ Regeneration, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
³ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
⁴ Center of Regenerative Medicine in Barcelona, Doctor Aiguader 88, 08003 Barcelona, Spain.
⁵ Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

^* Author for correspondence (e-mail: suzukicks{at}bioreg.kyushu-u.ac.jp)

Accepted 25 February 2008

SUMMARY

Although the T-box family of transcription factors function in many different tissues, their role in liver development is unknown. Here we show that Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome, is specifically expressed in multipotent hepatic progenitor cells, `hepatoblasts', isolated from the developing mouse liver. Tbx3-deficient hepatoblasts presented severe defects in proliferation as well as uncontrollable hepatobiliary lineage segregation, including the promotion of cholangiocyte (biliary epithelial cell) differentiation, which thereby caused abnormal liver development. Deletion of Tbx3 resulted in the increased expression of the tumor suppressor p19^ARF (Cdkn2a), which in turn induced a growth arrest in hepatoblasts and activated a program of cholangiocyte differentiation. Thus, Tbx3 plays a crucial role in controlling hepatoblast proliferation and cell-fate determination by suppressing p19^ARF expression and thereby promoting liver organogenesis.

Key words: Tbx3, Liver, Hepatoblast, p19^ARF (Cdkn2a), Differentiation, Mouse

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