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The discovery of the microphthalmia locus and its gene, Mitf.

ABSTRACT: The history of the discovery of the microphthalmia locus and its gene, now called Mitf, is a testament to the triumph of serendipity. Although the first microphthalmia mutation was discovered among the descendants of a mouse that was irradiated for the purpose of mutagenesis, the mutation most likely was not radiation induced but occurred spontaneously in one of the parents of a later breeding. Although Mitf might eventually have been identified by other molecular genetic techniques, it was first cloned from a chance transgene insertion at the microphthalmia locus. And although Mitf was found to encode a member of a well-known transcription factor family, its analysis might still be in its infancy had Mitf not turned out to be of crucial importance for the physiology and pathology of many distinct organs, including eye, ear, immune system, bone, and skin, and in particular for melanoma. In fact, near seven decades of Mitf research have led to many insights about development, function, degeneration, and malignancies of a number of specific cell types, and it is hoped that these insights will one day lead to therapies benefitting those afflicted with diseases originating in these cell types.

SUBMITTER: Arnheiter H

PROVIDER: S-EPMC2964399 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The discovery of the microphthalmia locus and its gene, Mitf.

Arnheiter Heinz H

Pigment cell & melanoma research 20100902 6

The history of the discovery of the microphthalmia locus and its gene, now called Mitf, is a testament to the triumph of serendipity. Although the first microphthalmia mutation was discovered among the descendants of a mouse that was irradiated for the purpose of mutagenesis, the mutation most likely was not radiation induced but occurred spontaneously in one of the parents of a later breeding. Although Mitf might eventually have been identified by other molecular genetic techniques, it was firs ...[more]

PMID: 20807369

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Project description:BackgroundThe diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment. We have previously demonstrated that the morphological and functional phenotypes of melanoma can be dynamically altered upon external stimuli.FindingsIn the present study, transcriptome profiles were generated to explore the molecules governing phenotypes of melanospheres grown in the bFGF(+)EGF(+) serum-free cultures and monolayers maintained in the serum-containing medium. Higher expression levels of MITF-dependent genes that are responsible for differentiation, e.g., TYR and MLANA, and stemness-related genes, e.g., ALDH1A1, were detected in melanospheres. These results were supported by the observation that the melanospheres contained more pigmented cells and cells exerting the self-renewal capacity than the monolayers. In addition, the expression of the anti-apoptotic, MITF-dependent genes e.g., BCL2A1 was also higher in the melanospheres. The enhanced activity of MITF in melanospheres, as illustrated by the increased expression of 74 MITF-dependent genes, identified MITF as a central transcriptional regulator in melanospheres. Importantly, several genes including MITF-dependent ones were expressed in melanospheres and original tumors at similar levels. The reduced MITF level in monolayers might be partially explained by suppression of the Wnt/β-catenin pathway, and DKK1, a secreted inhibitor of this pathway, was highly up-regulated in monolayers in comparison to melanospheres and original tumors. Furthermore, the silencing of DKK1 in monolayers increased the percentage of cells with self-renewing capacity.ConclusionsOur study indicates that melanospheres can be used to unravel the molecular pathways that sustain intratumoral phenotypic heterogeneity. Melanospheres directly derived from tumor specimens more accurately mirrored the morphology and gene expression profiles of the original tumors compared to monolayers. Therefore, melanospheres represent a relevant preclinical tool to study new anticancer treatment strategies.

Project description:Microphthalmia-associated transcription factor (Mitf) is expressed in neural crest cell-derived melanocytes, and in the retinal pigment epithelium (RPE) during ocular development. Mutations in Mitf are associated with auditory/visual/pigmentary syndromes in humans. Mitf(mi/mi) mouse mutants lack pigmentation, and are microphthalmic, while Mitf(vit/vit) mouse mutants display abnormal RPE pigmentation, and progressive retinal degeneration. Microarray analysis was used to identify novel downstream gene targets/pathways in the RPE that are altered by mutations in the transcription factor Mitf. Using the Affymetrix platform, gene expression profiles were generated using the eyes of E13.5 mouse fetuses that were wildtype, heterozygous, or homozygous for the Mitf(mi) mutation. In a separate experiment, eyes from E13.5 mouse fetuses homozygous for the Mitf(vit) mutation were compared to eyes from the C57BL/6 control background strain. Statistical analyses were performed using robust multiarray average, mixed-effects ANOVA and random-variance t-tests. Altered expression of genes involved in pigment formation, melanosome biogenesis/transport, and redox homeostasis were observed. Twelve genes were commonly mis-regulated in the eyes of both Mitf mutants: 10 of these genes were downregulated in both mutants relative to controls, while 2 of the genes (Nramp1 (Slc11a1) and epoxide hydrolase) were downregulated in Mitf(mi/mi) mutants, and conversely, upregulated in Mitf(vit/vit) mutants. Quantitative RT-PCR and immunohistochemistry were used to confirm altered gene/protein expression. RPE expression of the Fe(+2) iron transporter Nramp1 (Slc11a1) has not previously been reported. Fe(+2) is an important co-factor utilized by the iron-dependent isomerohydrolase RPE65 in the retinoid visual cycle. However, excess accumulation of Fe(+2) in the RPE has recently been associated with oxidative damage and age-related macular degeneration. Abnormal pigmentation and increased activity of Slc11a1 in the RPE of Mitf(vit) mice may contribute to the pathology and progressive retinal degeneration observed in these mutants.

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The discovery of the microphthalmia locus and its gene, Mitf.

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The discovery of the microphthalmia locus and its gene, Mitf.

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