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Molecular and Cellular Biology, December 1999, p. 8272-8280, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Paired-Homeodomain Transcription Factor PAX4 Acts as a Transcriptional Repressor in Early Pancreatic Development

Stuart B. Smith,1 Hooi C. Ee,1,dagger Jennifer R. Conners,1 and Michael S. German1,2,*

Hormone Research Institute1 and Department of Medicine,2 University of California, San Francisco, San Francisco, California 94143-0534

Received 25 March 1999/Returned for modification 20 May 1999/Accepted 16 August 1999

The paired-homeodomain transcription factor PAX4 is expressed in the developing pancreas and along with PAX6 is required for normal development of the endocrine cells. In the absence of PAX4, the numbers of insulin-producing beta  cells and somatostatin-producing delta  cells are drastically reduced, while the numbers of glucagon-producing alpha  cells are increased. To gain insight into PAX4 function, we cloned a full-length Pax4 cDNA from a beta -cell cDNA library and identified a bipartite consensus DNA binding sequence consisting of a homeodomain binding site separated from a paired domain binding site by 15 nucleotides. The paired half of this consensus sequence has similarities to the PAX6 paired domain consensus binding site, and the two proteins bind to common sequences in several islet genes, although with different relative affinities. When expressed in an alpha -cell line, PAX4 represses transcription through the glucagon or insulin promoters or through an isolated PAX4 binding site. This repression is not simply due to competition with the PAX6 transcriptional activator for the same binding site, since PAX4 fused to the unrelated yeast GAL4 DNA binding domain also represses transcription through the GAL4 binding site in the alpha -cell line and to a lesser degree in beta -cell lines and NIH 3T3 cells. Repressor activity maps to more than one domain within the molecule, although the homeodomain and carboxyl terminus give the strongest repression. PAX4 transcriptional regulation apparently plays a role only early in islet development, since Pax4 mRNA as determined by reverse transcriptase PCR peaks at embryonic day 13.5 in the fetal mouse pancreas and is undetectable in adult islets. In summary, PAX4 can function as a transcriptional repressor and is expressed early in pancreatic development, which may allow it to suppress alpha -cell differentiation and permit beta -cell differentiation.

* Corresponding author. Mailing address: Hormone Research Institute, University of California, San Francisco, San Francisco, CA 94143-0534. Phone: (415) 476-9262. Fax: (415) 731-3612. E-mail: german{at}cgl.ucsf.edu.

dagger Present address: Gastroenterology Department, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.

Molecular and Cellular Biology, December 1999, p. 8272-8280, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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