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Distinct and Shared Transcriptomes Are Regulated by Microphthalmia-Associated Transcription Factor Isoforms in Mast Cells¹

Amir H. Shahlaee^2,*, Stephanie Brandal^*, Youl-Nam Lee^*, Chunfa Jie and Clifford M. Takemoto^3,*

^* Division of Pediatric Hematology, Johns Hopkins Medical Institutions Microarray Core Facility, Johns Hopkins University, Baltimore, MD 21205

The Microphthalmia-associated transcription factor (Mitf) is an essential basic helix-loop-helix leucine zipper transcription factor for mast cell development. Mice deficient in Mitf harbor a severe mast cell deficiency, and Mitf-mutant mast cells cultured ex vivo display a number of functional defects. Therefore, an understanding of the genetic program regulated by Mitf may provide important insights into mast cell differentiation. Multiple, distinct isoforms of Mitf have been identified in a variety of cell types; we found that Mitf-a, Mitf-e, and Mitf-mc were the major isoforms expressed in mast cells. To determine the physiologic function of Mitf in mast cells, we restored expression of these isoforms in primary mast cells from Mitf^–/– mice. We found that these isoforms restored granular morphology and integrin-mediated migration. By microarray analysis, proteases, signaling molecules, cell surface receptor, and transporters comprised the largest groups of genes up-regulated by all isoforms. Furthermore, we found that isoforms also regulated distinct genes sets, suggesting separable biological activities. This work defines the transcriptome regulated by Mitf in mast cells and supports its role as master regulator of mast cell differentiation. Expression of multiple isoforms of this transcription factor may provide for redundancy of biological activities while also allowing diversity of function.

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.

¹ This work was supported in part by the Basil O’Conner Starter Scholar Research Award Grant 5-FY04-30 from the March of Dimes Birth Defects Foundation; a Children’s Cancer Foundation Grant; and National Institutes of Health Grant 5R01HL077178.

² Current address: Division of Pediatric Hematology and Oncology, University of Florida Health Science Center, Gainesville, FL 32610.

³ Address correspondence and reprint requests to Dr. Clifford Takemoto, Division of Pediatric Hematology, Johns Hopkins University, Baltimore, MD 21205. E-mail address: ctakemot{at}jhmi.edu

⁴ Abbreviations used in this paper: Mitf, Microphthalmia-associated transcription factor; SCF, stem cell factor; BMMC, bone marrow-derived mast cell; mMCP, mouse mast cell protease; C_T, cycle threshold; SSC, side scatter; RSK, ribosomal S6 kinase; Vla4, very late activation protein receptor 4.

⁵ The online version of this article contains supplemental material.

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