A chemical screen in zebrafish embryonic cells establishes that Akt activation is required for neural crest development

The neural crest is a dynamic progenitor cell population that arises at the border of neural and non-neural ectoderm. The inductive roles of FGF, Wnt, and BMP at the neural plate border are well established, but the signals required for subsequent neural crest development remain poorly characterized. Here, we conducted a screen in primary zebrafish embryo cultures for chemicals that disrupt neural crest development, as read out by crestin:EGFP expression. We found that the natural product caffeic acid phenethyl ester (CAPE) disrupts neural crest gene expression, migration, and melanocytic differentiation by reducing Sox10 activity. CAPE inhibits FGF-stimulated PI3K/Akt signaling, and neural crest defects in CAPE-treated embryos are suppressed by constitutively active Akt1. Inhibition of Akt activity by constitutively active PTEN similarly decreases crestin expression and Sox10 activity. Our study has identified Akt as a novel intracellular pathway required for neural crest differentiation.

• Publication year

  2017

• Venue

  eLife

• Publication date

  2017-08-23

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.7554/eLife.29145PMID 28832322PMCID 5599238
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Sox10 contributes to the balance of fate choice in dorsal root ganglion progenitors

  2017cited by this paper
• Embryonic cell culture in zebrafish.

  2016cited by this paper
• A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation

  2016influential reference
• Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration

  2016cited by this paper
• Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis

  2016cited by this paper
• PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis

  2015cited by this paper
• Leader cells regulate collective cell migration via Rac activation in the downstream signaling of integrin β1 and PI3K

  2015cited by this paper
• Neural crest migration is driven by a few trailblazer cells with a unique molecular signature narrowly confined to the invasive front

  2015cited by this paper
• Featured Article: Characterization of cultured multipotent zebrafish neural crest cells

  2014cited by this paper
• Caffeic acid phenethyl ester inhibits alpha-melanocyte stimulating hormone-induced melanin synthesis through suppressing transactivation activity of microphthalmia-associated transcription factor.

  2013cited by this paper
• Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.

  2013influential reference
• MEK1 Is Required for PTEN Membrane Recruitment, AKT Regulation, and the Maintenance of Peripheral Tolerance

  2013influential reference
• Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position

  2013cited by this paper
• Embryonic Fate Map of First Pharyngeal Arch Structures in the sox10: kaede Zebrafish Transgenic Model

  2012cited by this paper
• MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors.

  2012cited by this paper
• FGF signaling transforms non-neural ectoderm into neural crest.

  2012cited by this paper
• FGF/MAPK signaling is required in the gastrula epiblast for avian neural crest induction

  2012cited by this paper
• Ubiquitous transgene expression and Cre-based recombination driven by the ubiquitin promoter in zebrafish

  2011cited by this paper
• Zebrafish wnt9a is expressed in pharyngeal ectoderm and is required for palate and lower jaw development.

  2011cited by this paper
• FGF and retinoic acid activity gradients control the timing of neural crest cell emigration in the trunk

  2011cited by this paper
• Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

  2010influential reference
• Fibroblast growth factor signalling: from development to cancer

  2010cited by this paper
• PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

  2010cited by this paper
• Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells

  2009cited by this paper
• Foxd3 controls melanophore specification in the zebrafish neural crest by regulation of Mitf.

  2009cited by this paper
• Hairy 2 – Id 3 interactions play an essential role in Xenopus neural crest progenitor speci fi cation

  2009cited by this paper
• Fgf8a induces neural crest indirectly through the activation of Wnt8 in the paraxial mesoderm

  2008cited by this paper
• Transparent adult zebrafish as a tool for in vivo transplantation analysis.

  2008cited by this paper
• A gene regulatory network orchestrates neural crest formation

  2008cited by this paper
• Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

  2008influential reference
• Characterization of housekeeping genes in zebrafish: male-female differences and effects of tissue type, developmental stage and chemical treatment

  2008influential reference
• Zebrafish pten genes have overlapping and non-redundant functions in tumorigenesis and embryonic development

  2008cited by this paper
• Hairy2-Id3 interactions play an essential role in Xenopus neural crest progenitor specification.

  2008cited by this paper
• Phosphorylation of β-Catenin by AKT Promotes β-Catenin Transcriptional Activity*

  2007cited by this paper
• High-resolution in situ hybridization to whole-mount zebrafish embryos

  2007cited by this paper
• Gateway compatible vectors for analysis of gene function in the zebrafish

  2007cited by this paper
• Generation of FGF reporter transgenic zebrafish and their utility in chemical screens

  2007cited by this paper
• Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: Involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs.

  2006cited by this paper
• Neural crest determination by co-activation of Pax3 and Zic1 genes in Xenopus ectoderm

  2005cited by this paper
• Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction.

  2005cited by this paper
• Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma

  2005cited by this paper
• Reiterated Wnt signaling during zebrafish neural crest development

  2004cited by this paper
• FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.

  2004cited by this paper
• Transcriptional regulation of mitfa accounts for the sox10 requirement in zebrafish melanophore development

  2003cited by this paper
• Cell autonomous requirement for PDGFRα in populations of cranial and cardiac neural crest cells

  2003cited by this paper
• Ectodermal Wnt Function as a Neural Crest Inducer

  2002cited by this paper
• ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase*

  2002cited by this paper
• The phosphoinositide 3-kinase pathway.

  2002cited by this paper
• Platelet-derived growth factor receptor alpha (pdgfr-alpha) gene in zebrafish embryonic development.

  2002cited by this paper
• Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates.

  2001cited by this paper
• Genes dependent on zebrafish cyclops function identified by AFLP differential gene expression screen

  2000cited by this paper
• Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.

  2000influential reference
• Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3

  2000influential reference
• Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret.

  2000influential reference
• Regulation of G 1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase y Akt pathway

  1999cited by this paper
• Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway.

  1999cited by this paper
• The zebrafish Pax3 and Pax7 homologues are highly conserved, encode multiple isoforms and show dynamic segment-like expression in the developing brain.

  1998cited by this paper
• An essential role of phosphatidylinositol 3-kinase in myogenic differentiation.

  1998cited by this paper
• Expression of snail2, a second member of the zebrafish snail family, in cephalic mesendoderm and presumptive neural crest of wild-type and spadetail mutant embryos.

  1995cited by this paper
• Stages of embryonic development of the zebrafish

  1995cited by this paper
• Fgf 8 a induces neural crest indirectly through the activation of Wnt 8 in the paraxial mesoderm

  year unknowncited by this paper
• Pax 3 is required for enteric ganglia formation and functions with Sox 10 to modulate expression of cret

  year unknowninfluential reference
• A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox 10 in the otic vesicle

  year unknowncited by this paper

• The E3 Ubiquitin Ligase DCAF13 Is Essential for Craniofacial Development

  2026cites this paper
• High-throughput drug screening in advanced pre-clinical 3D melanoma models identifies potential first-line therapies for NRAS-mutated melanoma

  2025cites this paper
• Dis3l2 is essential for neural crest survival by modulating Akt signaling

  2025cites this paper
• Collective migration in complex environments: The case of the trunk neural crest.

  2025cites this paper
• Exploring the impact of MDMA and oxytocin ligands on anxiety and social responses: A comprehensive behavioural and molecular study in the zebrafish model

  2025cites this paper
• The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia—A Promising Road Ahead

  2025cites this paper
• Nf2/FGFR1/AKT axis directs cranial neural crest–derived skull morphogenesis via collagen synthesis and trafficking

  2025cites this paper
• BF170 hydrochloride enhances the emergence of hematopoietic stem and progenitor cells.

  2024cites this paper
• Construction of tissue engineered cornea with skin-derived corneal endothelial-like cell and mechanism research for the cell differentiation

  2024cites this paper
• Establishment and transcriptome analysis of single blastomere-derived cell lines from zebrafish.

  2024cites this paper
• Deciphering the enigma of the function of alpha-tocopherol as a vitamin.

  2024cites this paper
• The interplay of common genetic variants NRG1 rs2439302 and RET rs2435357 increases the risk of developing Hirschsprung’s disease

  2023cites this paper
• Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signalling

  2023cites this paper
• Mechanical dissection and culture of mouse cranial neural crest cells

  2023cites this paper
• Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signaling

  2022cites this paper
• Research Techniques Made Simple: Zebrafish Models for Human Dermatologic Disease.

  2022cites this paper
• Glucocorticoid receptor activation reduces food intake independent of hyperglycemia in zebrafish

  2022cites this paper
• Oxamyl exerts developmental toxic effects in zebrafish by disrupting the mitochondrial electron transport chain and modulating PI3K/Akt and p38 Mapk signaling.

  2022cites this paper
• Loss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion

  2022cites this paper
• Review: The Role of Wnt/β-Catenin Signalling in Neural Crest Development in Zebrafish

  2021cites this paper
• The crucial role of model systems in understanding the complexity of cell signaling in human neurocristopathies.

  2021cites this paper
• Expanding role of vitamin E in protection against metabolic dysregulation: Insights gained from model systems, especially the developing nervous system of zebrafish embryos.

  2021cites this paper
• Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials

  2021cites this paper
• Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development

  2021cites this paper
• Molecular Identification of Phytochemical for Anticancer Treatment.

  2020cites this paper
• From Tank to Treatment: Modeling Melanoma in Zebrafish

  2020cites this paper
• Vitamin E is necessary for zebrafish nervous system development

  2020cites this paper
• Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors

  2020cites this paper
• Akt is required for artery formation during embryonic vascular development

  2020cites this paper
• Brainstem Organoids From Human Pluripotent Stem Cells

  2020cites this paper
• Natural products as important tyrosine kinase inhibitors.

  2019cites this paper
• Brainstem organoids from human pluripotent stem cells contain neural crest population

  2019cites this paper
• The RNA helicase DDX3 induces neural crest by promoting AKT activity

  2019cites this paper
• Cell-Based Fish: A Novel Approach to Seafood Production and an Opportunity for Cellular Agriculture

  2018cites this paper
• MAPK and PI3K signaling: At the crossroads of neural crest development.

  2018cites this paper
• Specifying neural crest cells: From chromatin to morphogens and factors in between

  2018cites this paper