Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF
Author:
Bharti Kapil1, Liu Wenfang1, Csermely Tamas1, Bertuzzi Stefano1, Arnheiter Heinz1
Affiliation:
1. Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892,USA.
Abstract
During vertebrate eye development, the transcription factor MITF plays central roles in neuroepithelial domain specification and differentiation of the retinal pigment epithelium. MITF is not a single protein but represents a family of isoforms generated from a common gene by alternative promoter/exon use. To address the question of the role and regulation of these isoforms, we first determined their expression patterns in developing mouse eyes and analyzed the role of some of them in genetic models. We found that two isoforms, A- and J-Mitf, are present throughout development in both retina and pigment epithelium, whereas H-Mitf is detected preferentially and D-Mitf exclusively in the pigment epithelium. We further found that a genomic deletion encompassing the promoter/exon regions of H-, D- and B-Mitf leads to novel mRNA isoforms and proteins translated from internal start sites. These novel proteins lack the normal, isoform-specific N-terminal sequences and are unable to support the development of the pigment epithelium, but are capable of inducing pigmentation in the ciliary margin and the iris. Moreover, in mutants of the retinal Mitf regulator Chx10 (Vsx2),reduced cell proliferation and abnormal pigmentation of the retina are associated with a preferential upregulation of H- and D-Mitf. This retinal phenotype is corrected when H- and D-Mitf are missing in double Mitf/Chx10 mutants. The results suggest that Mitf regulation in the developing eye is isoform-selective, both temporally and spatially, and that some isoforms, including H- and D-Mitf, are more crucial than others in effecting normal retina and pigment epithelium development.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference35 articles.
1. Amae, S., Fuse, N., Yasumoto, K., Sato, S., Yajima, I.,Yamamoto, H., Udono, T., Durlu, Y. K., Tamai, M., Takahashi, K. et al.(1998). Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium. Biochem. Biophys. Res. Commun.247,710-715. 2. Arnheiter, H., Hou, L., Nguyen, M. T. T., Bismuth, K., Csermely,T., Murakami, H., Skuntz, S., Liu, W. and Bharti, K. (2006). Mitf - a matter of life and death for the developing melanocyte. In From Melanocytes to Melanoma: The progression to Malignancy (ed. V. Hearing and S. P. L. Leong), pp.27-49. Totowa, NJ: Humana Press. 3. Bäumer, N., Marquardt, T., Stoykova, A., Spieler, D.,Treichel, D., Ashery-Padan, R. and Gruss, P. (2003). Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6. Development130,2903-2915. 4. Bejar, J., Hong, Y. and Schartl, M. (2003). Mitf expression is sufficient to direct differentiation of medaka blastula derived stem cells to melanocytes. Development130,6545-6553. 5. Bharti, K., Nguyen, M. T., Skuntz, S., Bertuzzi, S. and Arnheiter, H. (2006). The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye. Pigment Cell Res.19,380-394.
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