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J. Biol. Chem., Vol. 281, Issue 16, 10799-10807, April 21, 2006

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Reduced Expression of the Endothelin Receptor Type B Gene in Piebald Mice Caused by Insertion of a Retroposon-like Element in Intron 1^*

Takahisa Yamada¹, Shin Ohtani, Takeshi Sakurai, Takehito Tsuji, Tetsuo Kunieda, and Masashi Yanagisawa²

From the Howard Hughes Medical Institute and the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050 and the Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan

Mice carrying the piebald mutation exhibit white coat spotting due to the regional absence of neural crest-derived melanocytes. We reported previously that the piebald locus encodes the Ednrb gene and that piebald mice express low levels of structurally intact Ednrb mRNA and EDNRB protein (Hosoda, K., Hammer, R. E., Richardson, J. A., Baynash, A. G., Cheung, J. C., Giaid, A., and Yanagisawa, M. (1994) Cell 79, 1267–1276). Here, we report that both the life span of the Ednrb mRNA and the promoter activity of the Ednrb gene are indistinguishable between wild-type and piebald mice. Introns 2–6 of the Ednrb gene in piebald mice were correctly excised with an efficiency indistinguishable from those in wild-type mice in exon trapping experiments. We found that the piebald allele of the Ednrb gene has a 5.5-kb retroposon-like element in intron 1 possessing canonical sequences of a polyadenylation signal and a splice acceptor site. Abnormal hybrid transcripts carrying exon 1 of the Ednrb gene and a portion of the 5.5-kb element are expressed in piebald mice. The insertion of the 5.5-kb element into a heterologous intron in a mammalian expression vector markedly reduced the expression of the reporter gene. Premature termination and aberrant splicing of the Ednrb transcript caused by the retroposon-like element in intron 1 lead to a reduced level of the normal Ednrb transcript, which is responsible for the partial loss-of-function phenotype of piebald mice.

Received for publication, November 28, 2005 , and in revised form, February 24, 2006.

^* This work was supported in part by research grants from the Perot Family Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB242436 [GenBank] .

¹ To whom correspondence may be addressed: Laboratory of Animal Breeding and Genetics, Graduate School of Agriculture, Kyoto University, Sakyoku, Kyoto 606-8502, Japan. Tel.: 81-75-753-6323; Fax: 81-75-753-6340; E-mail: tyamada{at}kais.kyoto-u.ac.jp. ² To whom correspondence may be addressed: Howard Hughes Medical Inst. and Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9050. Tel.: 214-648-5082; Fax: 214-648-5068; E-mail: masashi.yanagisawa{at}utsouthwestern.edu.

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