Dataset Information

Interspecies difference in the regulation of melanocyte development by SOX10 and MITF.

ABSTRACT: There is increasing indication that interspecific phenotypic differences result from variations in gene-regulatory interactions. Here we provide evidence that mice differ from zebrafish in the way they use homologous key components to regulate pigment cell differentiation. In both zebrafish and mice, one transcription factor, SOX10, controls the expression of another, MITF (microphthalmia-associated transcription factor), which in turn regulates a set of genes critical for pigment cell development and pigmentation. Mutations in either Sox10 or Mitf impair pigment cell development. In Sox10-mutant zebrafish, experimentally induced expression of Mitf fully rescues pigmentation. Using lineage-directed gene transfer, we show that, in the mouse, Mitf can rescue Sox10-mutant precursor cells only partially. In fact, retrovirally mediated, Sox10-independent Mitf expression in mouse melanoblasts leads to cell survival and expression of a number of pigment biosynthetic genes but does not lead to expression of tyrosinase, the rate-limiting pigment gene which critically depends on both Sox10 and Mitf. Hence, compared with fish, mice have evolved a regulation of tyrosinase expression that includes feed-forward loops between Sox10 and tyrosinase regulatory regions. The results may help to explain how some embryos, such as zebrafish, can achieve rapid pigmentation after fertilization, whereas others, such as mice, become pigmented only several days after birth.

SUBMITTER: Hou L

PROVIDER: S-EPMC1482569 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Interspecies difference in the regulation of melanocyte development by SOX10 and MITF.

Hou Ling L Arnheiter Heinz H Pavan William J WJ

Proceedings of the National Academy of Sciences of the United States of America 20060606 24

There is increasing indication that interspecific phenotypic differences result from variations in gene-regulatory interactions. Here we provide evidence that mice differ from zebrafish in the way they use homologous key components to regulate pigment cell differentiation. In both zebrafish and mice, one transcription factor, SOX10, controls the expression of another, MITF (microphthalmia-associated transcription factor), which in turn regulates a set of genes critical for pigment cell developme ...[more]

PMID: 16757562

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Project description:Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC.

Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the "master regulator" of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.

Dataset Information

Interspecies difference in the regulation of melanocyte development by SOX10 and MITF.

Publications

Interspecies difference in the regulation of melanocyte development by SOX10 and MITF.

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