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Molecular and Cellular Biology, November 2001, p. 7380-7390, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7380-7390.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

claudin-18, a Novel Downstream Target Gene for the T/EBP/NKX2.1 Homeodomain Transcription Factor, Encodes Lung- and Stomach-Specific Isoforms through Alternative Splicing

Tomoaki Niimi,1,dagger Kunio Nagashima,2 Jerrold M. Ward,3 Parviz Minoo,4 Drazen B. Zimonjic,5 Nicholas C. Popescu,5 and Shioko Kimura1,*

Laboratory of Metabolism1 and Laboratory of Experimental Carcinogenesis,5 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; EM Facility/Image Analysis Laboratory, SAIC Frederick,2 and Veterinary and Tumor Pathology Section, Office of Laboratory Animal Resources, National Cancer Institute,3 Frederick, Maryland 21702-1201; and Department of Pediatrics, Women's & Children's Hospital, USC School of Medicine, Los Angeles, California 900334

Received 13 March 2001/Returned for modification 13 April 2001/Accepted 3 August 2001

T/EBP/NKX2.1, a member of the NKX family of homeodomain-containing transcription factors, regulates the expression of a number of genes in lung and thyroid. Here we describe the isolation and characterization of a novel target gene, termed claudin-18, that is down-regulated in the lungs of T/ebp/Nkx2.1-null mouse embryos. The gene product exhibits an amino acid sequence similar to those of the claudin multigene family of proteins that constitute tight junction strands in epithelial cells. The gene was localized by fluorescence in situ hybridization to mouse chromosome 9 at region 9E3-F1 and to human chromosome 3 at region 3q21-23. The claudin-18 gene has two promoters, each with its own unique exon 1 that is spliced to common exons 2 through 5. Alternative usage of these promoters leads to production of lung and stomach-specific transcripts. The downstream lung-specific promoter contains two T/EBP/NKX2.1 binding sites responsible for trans activation of the gene by T/EBP/NKX2.1 in lung cells. Only claudin-18 was down-regulated in T/ebp/Nkx2.1-null embryo lungs among 11 claudin transcripts examined. Furthermore, the claudin-18 transcript has an alternative 12-bp insertion derived from the 5' end of intron 4, which produces a C-terminally truncated isoform in lung and stomach. Immunohistochemistry demonstrated complete membrane localization of claudin-18 with small focal dots in the lung and stomach epithelial cells. Immunogold electron microscopy analysis revealed that claudin-18 is concentrated at the cell-cell borders of epithelial cells. These unique features suggest a potentially important role for claudin-18 in the structure and function of tight junctions in lung and stomach.

* Corresponding author. Mailing address: Bldg. 37, Rm. 3E-24, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-0958. Fax: (301) 496-8419. E-mail: shioko{at}helix.nih.gov.

dagger Present address: Sekiguchi Biomatrix Signaling Project, ERATO, Japan Science and Technology Corporation, c/o Aichi Medical University, Aichi 480-1195, Japan.

Molecular and Cellular Biology, November 2001, p. 7380-7390, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7380-7390.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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