Transcription factors in melanocyte development: distinct roles for Pax-3 and Mitf.
A transgenic mouse model was used to examine the roles of the murine transcription factors Pax-3 and Mitf in melanocyte development. Transgenic mice expressing beta-galactosidase from the dopachrome tautomerase (Dct) promoter were generated and found to express the transgene in developing melanoblasts as early as embryonic day (E) 9.5. These mice express the transgene in a pattern characteristic of endogenous Dct expression. Transgenic mice were intercrossed with two murine coat color mutants, Splotch (Sp), containing a mutation in the murine Pax3 gene, and Mitf(mi), with a mutation in the basic-helix-loop-helix-leucine zipper gene Mitf. Transgenic heterozygous mutant animals were crossed to generate transgenic embryos for analysis. Examination of beta-galactosidase-expressing melanoblasts in mutant embryos reveals that Mitf is required in vivo for survival of melanoblasts up to the migration staging area in neural crest development. Examination of Mitf(mi)/+ embryos shows that there are diminished numbers of melanoblasts in the heterozygous state early in melanocyte development, consistent with a gene dosage-dependent effect upon cell survival. However, quantification and analysis of melanoblast growth during the migratory phase suggests that melanoblasts then increase in number more rapidly in the heterozygous embryo. In contrast to Mitf(mi)/Mitf(mi) embryos, Sp/Sp embryos exhibit melanoblasts that have migrated to characteristic locations along the melanoblast migratory pathway, but are greatly reduced in number compared to control littermates. Together, these results support a model for melanocyte development whereby Pax3 is required to expand a pool of committed melanoblasts or restricted progenitor cells early in development, whereas Mitf facilitates survival of the melanoblast in a gene dosage-dependent manner within and immediately after emigration from the dorsal neural tube, and may also directly or indirectly affect the rate at which melanoblast number increases during dorsolateral pathway migration.
The Ronald O. Perelman Department of Dermatology, New York University Medical Center, NY 10016, New York, USA. thornya1@smtpgw.is.hfh.edu
T J
TJ
Hornyak
D J
DJ
Hayes
L Y
LY
Chiu
E B
EB
Ziff
D000818:Animals; D002465:Cell Movement; D002470:Cell Survival; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006579:Heterozygote; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008297:Male; D008544:Melanocytes / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014157:Transcription Factors; D019076:Transgenes; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D001616:beta-Galactosidase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase