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Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858815/ https://www.ncbi.nlm.nih.gov/pubmed/31741801 http://dx.doi.org/10.7717/peerj.8054 |
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author | Cheng, Vanessa Dasgupta, Subham Reddam, Aalekhya Volz, David C. |
author_facet | Cheng, Vanessa Dasgupta, Subham Reddam, Aalekhya Volz, David C. |
author_sort | Cheng, Vanessa |
collection | PubMed |
description | Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone—a potent human PPARγ agonist—exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development. |
format | Online Article Text |
id | pubmed-6858815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68588152019-11-18 Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish Cheng, Vanessa Dasgupta, Subham Reddam, Aalekhya Volz, David C. PeerJ Developmental Biology Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone—a potent human PPARγ agonist—exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development. PeerJ Inc. 2019-11-13 /pmc/articles/PMC6858815/ /pubmed/31741801 http://dx.doi.org/10.7717/peerj.8054 Text en © 2019 Cheng et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. |
spellingShingle | Developmental Biology Cheng, Vanessa Dasgupta, Subham Reddam, Aalekhya Volz, David C. Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish |
title | Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish |
title_full | Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish |
title_fullStr | Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish |
title_full_unstemmed | Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish |
title_short | Ciglitazone—a human PPARγ agonist—disrupts dorsoventral patterning in zebrafish |
title_sort | ciglitazone—a human pparγ agonist—disrupts dorsoventral patterning in zebrafish |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858815/ https://www.ncbi.nlm.nih.gov/pubmed/31741801 http://dx.doi.org/10.7717/peerj.8054 |
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