Cargando…

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

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 xanthop...

Descripción completa

Detalles Bibliográficos
Autores principales: Petratou, Kleio, Subkhankulova, Tatiana, Lister, James A., Rocco, Andrea, Schwetlick, Hartmut, Kelsh, Robert N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191144/
https://www.ncbi.nlm.nih.gov/pubmed/30286071
http://dx.doi.org/10.1371/journal.pgen.1007402
_version_ 1783363671944069120
author Petratou, Kleio
Subkhankulova, Tatiana
Lister, James A.
Rocco, Andrea
Schwetlick, Hartmut
Kelsh, Robert N.
author_facet Petratou, Kleio
Subkhankulova, Tatiana
Lister, James A.
Rocco, Andrea
Schwetlick, Hartmut
Kelsh, Robert N.
author_sort Petratou, Kleio
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6191144
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-61911442018-10-25 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 Kelsh, Robert N. PLoS Genet Research Article 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. Public Library of Science 2018-10-04 /pmc/articles/PMC6191144/ /pubmed/30286071 http://dx.doi.org/10.1371/journal.pgen.1007402 Text en © 2018 Petratou et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Petratou, Kleio
Subkhankulova, Tatiana
Lister, James A.
Rocco, Andrea
Schwetlick, Hartmut
Kelsh, Robert N.
A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
title A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
title_full A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
title_fullStr A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
title_full_unstemmed A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
title_short A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
title_sort systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191144/
https://www.ncbi.nlm.nih.gov/pubmed/30286071
http://dx.doi.org/10.1371/journal.pgen.1007402
work_keys_str_mv AT petratoukleio asystemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT subkhankulovatatiana asystemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT listerjamesa asystemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT roccoandrea asystemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT schwetlickhartmut asystemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT kelshrobertn asystemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT petratoukleio systemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT subkhankulovatatiana systemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT listerjamesa systemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT roccoandrea systemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT schwetlickhartmut systemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest
AT kelshrobertn systemsbiologyapproachuncoversthecoregeneregulatorynetworkgoverningiridophorefatechoicefromtheneuralcrest