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A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest

Petratou, Kleio, Subkhankulova, Tatiana, Lister, James A., Rocco, Andrea, Schwetlick, Hartmut and Kelsh, Robert N. (2018) A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest PLOS Genetics, 14 (10), e1007402. pp. 1-32.

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Abstract

Multipotent neural crest (NC) progenitors generate an astonishing array of derivatives, including neuronal, skeletal components and pigment cells (chromatophores), but the molecular mechanisms allowing balanced selection of each fate remain unknown. In zebrafish, melanocytes, iridophores and xanthophores, the three chromatophore lineages, are thought to share progenitors and so lend themselves to investigating the complex gene regulatory networks (GRNs) underlying fate segregation of NC progenitors. Although the core GRN governing melanocyte specification has been previously established, those guiding iridophore and xanthophore development remain elusive. Here we focus on the iridophore GRN, where mutant phenotypes identify the transcription factors Sox10, Tfec and Mitfa and the receptor tyrosine kinase, Ltk, as key players. Here we present expression data, as well as loss and gain of function results, guiding the derivation of an initial iridophore specification GRN. Moreover, we use an iterative process of mathematical modelling, supplemented with a Monte Carlo screening algorithm suited to the qualitative nature of the experimental data, to allow for rigorous predictive exploration of the GRN dynamics. Predictions were experimentally evaluated and testable hypotheses were derived to construct an improved version of the GRN, which we showed produced outputs consistent with experimentally observed gene expression dynamics. Our study reveals multiple important regulatory features, notably a sox10-dependent positive feedback loop between tfec and ltk driving iridophore specification; the molecular basis of sox10 maintenance throughout iridophore development; and the cooperation between sox10 and tfec in driving expression of pnp4a, a key differentiation gene. We also assess a candidate repressor of mitfa, a melanocyte-specific target of sox10. Surprisingly, our data challenge the reported role of Foxd3, an established mitfa repressor, in iridophore regulation. Our study builds upon our previous systems biology approach, by incorporating physiologically-relevant parameter values and rigorous evaluation of parameter values within a qualitative data framework, to establish for the first time the core GRN guiding specification of the iridophore lineage.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Petratou, Kleio
Subkhankulova, Tatiana
Lister, James A.
Rocco, AndreaA.Rocco@surrey.ac.uk
Schwetlick, Hartmut
Kelsh, Robert N.
Date : 4 October 2018
Funders : Biotechnology and Biological Sciences Research Council (BBSRC)
DOI : 10.1371/journal.pgen.1007402
Grant Title : South West Biosciences Doctoral Training Partnership
Copyright Disclaimer : © 2018 Petratou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Contributors :
ContributionNameEmailORCID
http://www.loc.gov/loc.terms/relators/EDTParichy, David M.
Depositing User : Clive Harris
Date Deposited : 24 Sep 2019 14:27
Last Modified : 24 Sep 2019 14:43
URI: http://epubs.surrey.ac.uk/id/eprint/852772

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