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First published online 24 December 2003
doi: 10.1242/dev.00943
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1 Division of Biology, Center for Molecular Medicine, Jichi Medical School,
Tochigi 329-0498, Japan
2 Department of Molecular Neurobiology, Institute of Development, Aging and
Cancer, Tohoku University, Sendai 980-8575, Japan
3 Division of Transgenic Technology, Center for Animal Resources and
Development, Kumamoto University, Kumamoto 860-0811, Japan
4 Department of Otolaryngology, Tokyo Medical and Dental University, Tokyo
113-8519, Japan
5 Division of Nephrology, Department of Internal Medicine, Jichi Medical School,
Tochigi 329-0498, Japan
6 Division of Cell Biology, Center for Experimental Medicine, Institute of
Medical Science, University of Tokyo, Tokyo 108-8639, Japan
* Author for correspondence (e-mail: kkawakam{at}jichi.ac.jp)
Accepted 24 October 2003
Six1 is a member of the Six family homeobox genes, which function as components of the Pax-Six-Eya-Dach gene network to control organ development. Six1 is expressed in otic vesicles, nasal epithelia, branchial arches/pouches, nephrogenic cords, somites and a limited set of ganglia. In this study, we established Six1-deficient mice and found that development of the inner ear, nose, thymus, kidney and skeletal muscle was severely affected. Six1-deficient embryos were devoid of inner ear structures, including cochlea and vestibule, while their endolymphatic sac was enlarged. The inner ear anomaly began at around E10.5 and Six1 was expressed in the ventral region of the otic vesicle in the wild-type embryos at this stage. In the otic vesicle of Six1-deficient embryos, expressions of Otx1, Otx2, Lfng and Fgf3, which were expressed ventrally in the wild-type otic vesicles, were abolished, while the expression domains of Dlx5, Hmx3, Dach1 and Dach2, which were expressed dorsally in the wild-type otic vesicles, expanded ventrally. Our results indicate that Six1 functions as a key regulator of otic vesicle patterning at early embryogenesis and controls the expression domains of downstream otic genes responsible for respective inner ear structures. In addition, cell proliferation was reduced and apoptotic cell death was enhanced in the ventral region of the otic vesicle, suggesting the involvement of Six1 in cell proliferation and survival. In spite of the similarity of otic phenotypes of Six1- and Shh-deficient mice, expressions of Six1 and Shh were mutually independent.
Key words: Six1, Otic vesicle, Inner ear, Pattern formation, Cell proliferation, Shh, Mouse
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