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Molecular and Cellular Biology, April 2003, p. 2277-2286, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2277-2286.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Retinoic Acid Repression of Bone Morphogenetic Protein 4 in Inner Ear Development

Deborah L. Thompson,1 Lisa M. Gerlach-Bank,2,3,{dagger} Kate F. Barald,2,3 and Ronald J. Koenig1,2*

Department of Internal Medicine, Endocrinology Division,1 Cell and Molecular Biology Program,2 Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-06783

Received 19 November 2002/ Returned for modification 2 January 2003/ Accepted 8 January 2003

Bone morphogenetic protein 4 (BMP4) and retinoic acid are important for normal development of the inner ear, but whether they are linked mechanistically is not known. BMP4 antagonists disrupt semicircular canal formation, as does exposure to retinoic acid. We demonstrate that retinoic acid directly down-regulates BMP4 transcription in a mouse inner ear-derived cell line, and we identify a novel promoter in the second intron of the BMP4 gene that is a target of this regulation both in the cell line and in the mouse embryonic inner ear in vivo. The importance of this down-regulation is demonstrated in chicken embryos by showing that the retinoic acid effect on semicircular canal development can be overcome by exogenous BMP4.

* Corresponding author. Mailing address: 5560 MSRB2, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0678. Phone: (734) 763-3056. Fax: (734) 936-6684. E-mail: rkoenig{at}umich.edu.

{dagger} Present address: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-0678.

Molecular and Cellular Biology, April 2003, p. 2277-2286, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2277-2286.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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