Microphthalmia-associated transcription factor in the Wnt signaling pathway

Pigment Cell Res. 2003 Jun;16(3):261-5. doi: 10.1034/j.1600-0749.2003.00039.x.


Microphthalmia-associated transcription factor (MITF) contains a basic helix-loop-helix and leucine-zipper (bHLH-LZ) structure and consists of many isoforms with different N-termini. Melanocyte-specific MITF isoform (MITF-M) is of particular interest, because a heterozygous mutation in the MITF gene is associated with Waardenburg syndrome type 2 (WS2) that is characterized by deafness and hypopigmentation because of lack of melanocytes in the inner ear and skin. Expression of MITF-M is under the regulation of the melanocyte-specific promoter (M promoter) of the MITF gene, and transcription from the M promoter is induced by Wnt signals through a nuclear mediator, lymphoid-enhancing factor 1 (LEF-1). In addition, functional cooperation of MITF-M with LEF-1 could lead to transcriptional activation of the M promoter and the dopachrome tautomerase (DCT) gene, an early melanoblast marker. The bHLH-LZ region of MITF-M is responsible for the physical interaction with LEF-1, and beta-catenin is required for the collaboration between LEF-1 and MITF-M. Importantly, MITF-M could function as a non-DNA-binding co-factor for LEF-1. These results suggest that MITF-M may function as a self-regulator of its own expression to maintain a threshold level of MITF-M at a certain sensitive stage of melanocyte development, which could account for the dominant inheritance of WS2. MITF-M therefore plays dual roles in the Wnt signaling pathway; MITF-M represents a downstream target and a nuclear mediator of Wnt signals in melanocytes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Differentiation
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Exons
  • Gene Expression Regulation
  • Heterozygote
  • Humans
  • Intramolecular Oxidoreductases / genetics
  • Lymphoid Enhancer-Binding Factor 1
  • Melanocytes / metabolism
  • Mice
  • Microphthalmia-Associated Transcription Factor
  • Models, Biological
  • Models, Genetic
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin


  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LEF1 protein, human
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Mitf protein, mouse
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • Intramolecular Oxidoreductases
  • dopachrome isomerase