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.

Fig. 1

Paula Hertwig at the microscope (reproduced with permission from BIOspektrum)

Fig. 2

The vga-9 transgene insertion is allelic with microphthalmia-mi. Vga-9/+ hetero-zygotes were crossed with mi/+ heterozygotes, yielding white, microphthalmic mice that resembled mi/mi homozygotes and carried the vga-9 transgene (bottom mouse). The cross also generated pigmented mice that carried at least one wild-type microphthalmia allele (upper two mice). Photograph courtesy of Lesley Forrester.