Expansion of a neural crest gene signature following ectopic MYCN expression in sympathoadrenal lineage cells in vivo

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dc.citation.articleNumbere0310727en_US
dc.citation.issueNumber9en_US
dc.citation.journalTitlePLOS ONEen_US
dc.citation.volumeNumber19en_US
dc.contributor.authorIbarra-García-Padilla, Rodrigoen_US
dc.contributor.authorNambiar, Annikaen_US
dc.contributor.authorHamre, Thomas A.en_US
dc.contributor.authorSingleton, Eileen W.en_US
dc.contributor.authorUribe, Rosa A.en_US
dc.date.accessioned2024-10-08T13:28:37Zen_US
dc.date.available2024-10-08T13:28:37Zen_US
dc.date.issued2024en_US
dc.description.abstractNeural crest cells (NCC) are multipotent migratory stem cells that originate from the neural tube during early vertebrate embryogenesis. NCCs give rise to a variety of cell types within the developing organism, including neurons and glia of the sympathetic nervous system. It has been suggested that failure in correct NCC differentiation leads to several diseases, including neuroblastoma (NB). During normal NCC development, MYCN is transiently expressed to promote NCC migration, and its downregulation precedes neuronal differentiation. Overexpression of MYCN has been linked to high-risk and aggressive NB progression. For this reason, understanding the effect overexpression of this oncogene has on the development of NCC-derived sympathoadrenal progenitors (SAP), which later give rise to sympathetic nerves, will help elucidate the developmental mechanisms that may prime the onset of NB. Here, we found that overexpressing human EGFP-MYCN within SAP lineage cells in zebrafish led to the transient formation of an abnormal SAP population, which displayed expanded and elevated expression of NCC markers while paradoxically also co-expressing SAP and neuronal differentiation markers. The aberrant NCC signature was corroborated with in vivo time-lapse confocal imaging in zebrafish larvae, which revealed transient expansion of sox10 reporter expression in MYCN overexpressing SAPs during the early stages of SAP development. In these aberrant MYCN overexpressing SAP cells, we also found evidence of dampened BMP signaling activity, indicating that BMP signaling disruption occurs following elevated MYCN expression. Furthermore, we discovered that pharmacological inhibition of BMP signaling was sufficient to create an aberrant NCC gene signature in SAP cells, phenocopying MYCN overexpression. Together, our results suggest that MYCN overexpression in SAPs disrupts their differentiation by eliciting abnormal NCC gene expression programs, and dampening BMP signaling response, having developmental implications for the priming of NB in vivo.en_US
dc.identifier.citationIbarra-García-Padilla, R., Nambiar, A., Hamre, T. A., Singleton, E. W., & Uribe, R. A. (2024). Expansion of a neural crest gene signature following ectopic MYCN expression in sympathoadrenal lineage cells in vivo. PLOS ONE, 19(9), e0310727. https://doi.org/10.1371/journal.pone.0310727en_US
dc.identifier.digitaljournal-pone-0310727en_US
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0310727en_US
dc.identifier.urihttps://hdl.handle.net/1911/117937en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleExpansion of a neural crest gene signature following ectopic MYCN expression in sympathoadrenal lineage cells in vivoen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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