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Cited by 73Developmental Biology and Gene Regulationmelanin and skin pigmentationZebrafish Biomedical Research Applications

An Iterative Genetic and Dynamical Modelling Approach Identifies Novel Features of the Gene Regulatory Network Underlying Melanocyte Development

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Greenhill, Emma R., Rocco, Andrea, Vibert, Laura, Nikaido, Masataka, Kelsh, Robert N.·2011·PLoS Genetics
DOI 10.1371/journal.pgen.1002265PMC PMC3164703
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Abstract

The mechanisms generating stably differentiated cell-types from multipotent precursors are key to understanding normal development and have implications for treatment of cancer and the therapeutic use of stem cells. Pigment cells are a major derivative of neural crest stem cells and a key model cell-type for our understanding of the genetics of cell differentiation. Several factors driving melanocyte fate specification have been identified, including the transcription factor and master regulator of melanocyte development, Mitf, and Wnt signalling and the multipotency and fate specification factor, Sox10, which drive mitf expression. While these factors together drive multipotent neural crest cells to become specified melanoblasts, the mechanisms stabilising melanocyte differentiation remain unclear. Furthermore, there is controversy over whether Sox10 has an ongoing role in melanocyte differentiation. Here we use zebrafish to explore in vivo the gene regulatory network (GRN) underlying melanocyte specification and differentiation. We use an iterative process of mathematical modelling and experimental observation to explore methodically the core melanocyte GRN we have defined. We show that Sox10 is not required for ongoing differentiation and expression is downregulated in differentiating cells, in response to Mitfa and Hdac1. Unexpectedly, we find that Sox10 represses Mitf-dependent expression of melanocyte differentiation genes. Our systems biology approach allowed us to predict two novel features of the melanocyte GRN, which we then validate experimentally. Specifically, we show that maintenance of mitfa expression is Mitfa-dependent, and identify Sox9b as providing an Mitfa-independent input to melanocyte differentiation. Our data supports our previous suggestion that Sox10 only functions transiently in regulation of mitfa and cannot be responsible for long-term maintenance of mitfa expression; indeed, Sox10 is likely to slow melanocyte differentiation in the zebrafish embryo. More generally, this novel approach to understanding melanocyte differentiation provides a basis for systematic modelling of differentiation in this and other cell-types.

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  • Sox10, in conjunction with Wnt signalling, is required to activate and maintain mitfa transcription.

    “In this lineage, Sox10, in conjunction with Wnt signalling, is required to activate and maintain mitfa transcription [13, 20, 24–26].”

    From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [13]

    The Results section, “Overexpression of Mitfa, but not Sox10,” reports that Sox10 induces mitfa transcription, supporting the activation part. But the Discussion attributes maintenance of mitfa expression to Mitfa-dependent feedback, and the modelling Results describe that feedback as Sox10-independent. The paper mentions Wnt-related factors as possible inputs to sox10 regulation, not as an established joint requirement with Sox10 for activating and maintaining mitfa. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Mitfa is able to efficiently rescue melanocyte development in the absence of sox10 through triggering both an Mitfa autoregulatory feedback loop and expression of melanocyte differentiation genes.

    “For example, Mitfa is able to efficiently rescue melanocyte development in the absence of sox10 through triggering both an Mitfa autoregulatory feedback loop and expression of melanocyte differentiation genes [13, 25].”

    From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [13]

    The Results (pages unavailable) show that Mitfa overexpression induces melanocyte differentiation genes and endogenous mitfa expression; the Discussion interprets the latter as a positive feedback loop that may be indirect. But the paper does not show that Mitfa efficiently rescues melanocyte development in sox10 mutants. Its Results instead describe weak differentiation-gene expression in sox10;mitfa double mutants as Mitfa-independent. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Sox10 and Sox9b have previously been reported to act redundantly during zebrafish development.

    “Sox10 and Sox9b have previously been reported to act redundantly during zebrafish development [13, 22].”

    From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [13]

    In Results (‘Sox9b has the properties of Factor Z’; page unavailable), Sox9b knockdown reduces residual melanisation in sox10-mutant zebrafish embryos, showing that Sox9b can contribute when Sox10 is absent. The finding concerns early melanocyte development; the paper does not establish that the two act redundantly throughout zebrafish development. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Previously published experimental data show that maintenance of mitfa is restricted to melanocytes.

    “These predictions are in contrast to previously published experimental data, showing that maintenance of mitfa is restricted to melanocytes [21], [22], although lower level mitfa expression has been detected by RNA-seq in differentiated iridophores [48].”

    From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [22]

    The Discussion (page unavailable) reports evidence that Mitfa helps maintain mitfa expression during melanocyte differentiation. It does not establish that maintained expression is restricted to melanocytes; its discussion of iridophores concerns cells that initially turn on mitfa, not whether expression persists in them. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In melanocytes, Sox10 acts together with Wnt signalling to establish mitfa expression, but sox10 is then strongly downregulated; maintenance of expression is thought to promote multipotency and delay differentiation.

    “In melanocytes, Sox10 acts together with Wnt signalling to establish mitfa expression, but sox10 is then strongly downregulated, and indeed maintenance of expression is thought to promote multipotency and delay differentiation [22].”

    From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [22]

    The Results report that Sox10 induces mitfa and is rapidly downregulated in differentiating zebrafish melanocytes. The Discussion proposes that continued Sox10-mediated repression may delay differentiation and maintain precursor multipotency. The Results discuss Wnt-related factors as possible regulators of sox10, but do not establish that Wnt signalling acts together with Sox10 to initiate mitfa expression in melanocytes. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Greenhill, E. R., Rocco, A., Vibert, L., Nikaido, M., & Kelsh, R. N.
Affiliations
University of Bath (GB)
Corresponding author
Kelsh, Robert N.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2011-09-01
Volume
7
Issue
9
Pages
e1002265
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002265
PMC
PMC3164703
OpenAlex
W2107143931
Cited by
73
References
1
Citations by year
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FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Wellcome Trust (083770/Z/07/Z, 087870, 083770, 087870/Z/08/Z, 066326)
  • University of Bath
  • Medical Research Council
  • Biotechnology and Biological Sciences Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
Keywords
melanocyte differentiation, gene regulatory networks, SOX10, MITF, mitfa, sox9b, HDAC1, neural crest stem cells, melanoblasts, Wnt signaling, transcriptional repression, zebrafish embryos, cell fate specification
MeSH terms
Animals, Cell Differentiation, Melanocytes, Models, Theoretical, Neural Crest, Stem Cells, Zebrafish, Zebrafish Proteins, Microphthalmia-Associated Transcription Factor, Gene Regulatory Networks, SOXE Transcription Factors, SOX9 Transcription Factor, Histone Deacetylase 1, Wnt Signaling Pathway

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