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Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish
The mammalian Diaphanous-related (mDia) formins are cytoskeletal regulators that assemble and, in some cases, bundle filamentous actin (F-actin), as well as stabilize microtubules. The development of small molecule antagonists and agonists that interrogate mDia formin function has allowed us to inve...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902741/ https://www.ncbi.nlm.nih.gov/pubmed/29692731 http://dx.doi.org/10.3389/fphar.2018.00340 |
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author | LeCorgne, Hunter Tudosie, Andrew M. Lavik, Kari Su, Robin Becker, Kathryn N. Moore, Sara Walia, Yashna Wisner, Alexander Koehler, Daniel Alberts, Arthur S. Williams, Frederick E. Eisenmann, Kathryn M. |
author_facet | LeCorgne, Hunter Tudosie, Andrew M. Lavik, Kari Su, Robin Becker, Kathryn N. Moore, Sara Walia, Yashna Wisner, Alexander Koehler, Daniel Alberts, Arthur S. Williams, Frederick E. Eisenmann, Kathryn M. |
author_sort | LeCorgne, Hunter |
collection | PubMed |
description | The mammalian Diaphanous-related (mDia) formins are cytoskeletal regulators that assemble and, in some cases, bundle filamentous actin (F-actin), as well as stabilize microtubules. The development of small molecule antagonists and agonists that interrogate mDia formin function has allowed us to investigate the roles of formins in disease states. A small molecule inhibitor of FH2 domain (SMIFH2) inhibits mDia-dependent actin dynamics and abrogates tumor cell migration and cell division in vitro and ex vivo tissue explants. mDia formin activation with small molecule intramimics IMM01/02 and mDia2-DAD peptides inhibited glioblastoma motility and invasion in vitro and ex vivo rat brain slices. However, SMIFH2, IMMs, and mDia2 DAD efficacy in vivo remains largely unexplored and potential toxicity across a range of developmental phenotypes has not been thoroughly characterized. In this study, we performed an in vivo screen of early life-stage toxicity in Danio rerio zebrafish embryos 2 days post-fertilization (dpf) in response to SMIFH2, IMM01/02, and mDia2 DAD. SMIFH2 at concentrations ≥5–10 μM induced significant defects in developing zebrafish, including shorter body lengths, tail curvature and defective tail cellularity, craniofacial malformations, pericardial edema, absent and/or compromised vasculature function and flow, depressed heart rates and increased mortality. Conversely, IMM and mDia2 DAD peptides were minimally toxic at concentrations up to 10–20 and 50 μM, respectively. SMIFH2's therapeutic potential may therefore be limited by its substantial in vivo toxicity at functional concentrations. mDia formin agonism with IMMs and mDia2 DADs may therefore be a more effective and less toxic anti-invasive therapeutic approach. |
format | Online Article Text |
id | pubmed-5902741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59027412018-04-24 Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish LeCorgne, Hunter Tudosie, Andrew M. Lavik, Kari Su, Robin Becker, Kathryn N. Moore, Sara Walia, Yashna Wisner, Alexander Koehler, Daniel Alberts, Arthur S. Williams, Frederick E. Eisenmann, Kathryn M. Front Pharmacol Pharmacology The mammalian Diaphanous-related (mDia) formins are cytoskeletal regulators that assemble and, in some cases, bundle filamentous actin (F-actin), as well as stabilize microtubules. The development of small molecule antagonists and agonists that interrogate mDia formin function has allowed us to investigate the roles of formins in disease states. A small molecule inhibitor of FH2 domain (SMIFH2) inhibits mDia-dependent actin dynamics and abrogates tumor cell migration and cell division in vitro and ex vivo tissue explants. mDia formin activation with small molecule intramimics IMM01/02 and mDia2-DAD peptides inhibited glioblastoma motility and invasion in vitro and ex vivo rat brain slices. However, SMIFH2, IMMs, and mDia2 DAD efficacy in vivo remains largely unexplored and potential toxicity across a range of developmental phenotypes has not been thoroughly characterized. In this study, we performed an in vivo screen of early life-stage toxicity in Danio rerio zebrafish embryos 2 days post-fertilization (dpf) in response to SMIFH2, IMM01/02, and mDia2 DAD. SMIFH2 at concentrations ≥5–10 μM induced significant defects in developing zebrafish, including shorter body lengths, tail curvature and defective tail cellularity, craniofacial malformations, pericardial edema, absent and/or compromised vasculature function and flow, depressed heart rates and increased mortality. Conversely, IMM and mDia2 DAD peptides were minimally toxic at concentrations up to 10–20 and 50 μM, respectively. SMIFH2's therapeutic potential may therefore be limited by its substantial in vivo toxicity at functional concentrations. mDia formin agonism with IMMs and mDia2 DADs may therefore be a more effective and less toxic anti-invasive therapeutic approach. Frontiers Media S.A. 2018-04-10 /pmc/articles/PMC5902741/ /pubmed/29692731 http://dx.doi.org/10.3389/fphar.2018.00340 Text en Copyright © 2018 LeCorgne, Tudosie, Lavik, Su, Becker, Moore, Walia, Wisner, Koehler, Alberts, Williams and Eisenmann. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology LeCorgne, Hunter Tudosie, Andrew M. Lavik, Kari Su, Robin Becker, Kathryn N. Moore, Sara Walia, Yashna Wisner, Alexander Koehler, Daniel Alberts, Arthur S. Williams, Frederick E. Eisenmann, Kathryn M. Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish |
title | Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish |
title_full | Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish |
title_fullStr | Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish |
title_full_unstemmed | Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish |
title_short | Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish |
title_sort | differential toxicity of mdia formin-directed functional agonists and antagonists in developing zebrafish |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902741/ https://www.ncbi.nlm.nih.gov/pubmed/29692731 http://dx.doi.org/10.3389/fphar.2018.00340 |
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