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Molecular and Cellular Biology, April 2004, p. 2673-2681, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2673-2681.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Mist1 Homodimer Formation Induces Pancreatic Acinar-to-Ductal Metaplasia

Liqin Zhu, Thai Tran, J. Michael Rukstalis, Peichuan Sun, Barbara Damsz, and Stephen F. Konieczny*

Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907-1392

Received 31 October 2003/ Returned for modification 19 December 2003/ Accepted 6 January 2004

The pancreas consists of three main cell lineages (endocrine, exocrine, and duct) that develop from common primitive foregut precursors. The transcriptional network responsible for endocrine cell development has been studied extensively, but much less is known about the transcription factors that maintain the exocrine and duct cell lineages. One transcription factor that may be important to exocrine cell function is Mist1, a basic helix-loop-helix (bHLH) factor that is expressed in acinar cells. In order to perform a molecular characterization of this protein, we employed coimmunoprecipitation and bimolecular fluorescence complementation assays, coupled with electrophoretic mobility shift assay studies, to show that Mist1 exists in vivo as a homodimer complex. Analysis of transgenic mice expressing a dominant-negative Mist1 transgene (Mist1mutant basic [Mist1MB]) revealed the cell autonomous effect of inhibiting endogenous Mist1. Mist1MB cells become disorganized, exhibit a severe depletion of intercellular gap junctions, and express high levels of the glycoprotein clusterin, which has been shown to demarcate immature acinar cells. Inhibition of Mist1 transcriptional activity also leads to activation of duct-specific genes, such as cytokeratin 19 and cytokeratin 20, suggesting that alterations in the bHLH network produce a direct acinar-to-ductal phenotypic switch in mature cells. We propose that Mist1 is a key transcriptional regulator of exocrine pancreatic cells and that in the absence of functional Mist1, acinar cells do not maintain their normal identity.

* Corresponding author. Mailing address: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-1392. Phone: (765) 494-7976. Fax: (765) 496-2536. E-mail: sfk{at}bilbo.bio.purdue.edu.

Molecular and Cellular Biology, April 2004, p. 2673-2681, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2673-2681.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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