HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair
Embryonic exposure to the teratogen nicotine results in brain defects, by disrupting endogenous spatial pre patterns necessary for normal brain size and patterning. Extending prior work in Xenopus laevis that showed that misexpression of ion channels can rescue morphogenesis, we demonstrate and char...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2020.00136/full |
| _version_ | 1818308794343489536 |
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| author | Vaibhav P. Pai Javier Cervera Salvador Mafe Valerie Willocq Emma K. Lederer Michael Levin Michael Levin |
| author_facet | Vaibhav P. Pai Javier Cervera Salvador Mafe Valerie Willocq Emma K. Lederer Michael Levin Michael Levin |
| author_sort | Vaibhav P. Pai |
| collection | DOAJ |
| description | Embryonic exposure to the teratogen nicotine results in brain defects, by disrupting endogenous spatial pre patterns necessary for normal brain size and patterning. Extending prior work in Xenopus laevis that showed that misexpression of ion channels can rescue morphogenesis, we demonstrate and characterize a novel aspect of developmental bioelectricity: channel-dependent repair signals propagate long-range across the embryo. We show that distal HCN2 channel misexpression and distal transplants of HCN2-expressing tissue, non-cell-autonomously reverse profound defects, rescuing brain anatomy, gene expression, and learning. Moreover, such rescue can be induced by small-molecule HCN2 channel activators, even with delayed treatment initiation. We present a simple, versatile computational model of bioelectrical signaling upstream of key patterning genes such as OTX2 and XBF1, which predicts long-range repair induced by ion channel activity, and experimentally validate the predictions of this model. Our results and quantitative model identify a powerful morphogenetic control mechanism that could be targeted by future regenerative medicine exploiting ion channel modulating drugs approved for human use. |
| first_indexed | 2024-12-13T07:19:56Z |
| format | Article |
| id | doaj.art-587354ca633942958a0d48ad65f3fcdc |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-13T07:19:56Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-587354ca633942958a0d48ad65f3fcdc2022-12-21T23:55:27ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-05-011410.3389/fncel.2020.00136511704HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric RepairVaibhav P. Pai0Javier Cervera1Salvador Mafe2Valerie Willocq3Emma K. Lederer4Michael Levin5Michael Levin6Allen Discovery Center at Tufts University, Medford, MA, United StatesDepartament de Termodinamica, Facultat de Fisica, Universitat de Valencia, Burjassot, SpainDepartament de Termodinamica, Facultat de Fisica, Universitat de Valencia, Burjassot, SpainAllen Discovery Center at Tufts University, Medford, MA, United StatesAllen Discovery Center at Tufts University, Medford, MA, United StatesAllen Discovery Center at Tufts University, Medford, MA, United StatesWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United StatesEmbryonic exposure to the teratogen nicotine results in brain defects, by disrupting endogenous spatial pre patterns necessary for normal brain size and patterning. Extending prior work in Xenopus laevis that showed that misexpression of ion channels can rescue morphogenesis, we demonstrate and characterize a novel aspect of developmental bioelectricity: channel-dependent repair signals propagate long-range across the embryo. We show that distal HCN2 channel misexpression and distal transplants of HCN2-expressing tissue, non-cell-autonomously reverse profound defects, rescuing brain anatomy, gene expression, and learning. Moreover, such rescue can be induced by small-molecule HCN2 channel activators, even with delayed treatment initiation. We present a simple, versatile computational model of bioelectrical signaling upstream of key patterning genes such as OTX2 and XBF1, which predicts long-range repair induced by ion channel activity, and experimentally validate the predictions of this model. Our results and quantitative model identify a powerful morphogenetic control mechanism that could be targeted by future regenerative medicine exploiting ion channel modulating drugs approved for human use.https://www.frontiersin.org/article/10.3389/fncel.2020.00136/fullion channelbioelectricteratogennicotinenon-locallong-range |
| spellingShingle | Vaibhav P. Pai Javier Cervera Salvador Mafe Valerie Willocq Emma K. Lederer Michael Levin Michael Levin HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair Frontiers in Cellular Neuroscience ion channel bioelectric teratogen nicotine non-local long-range |
| title | HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair |
| title_full | HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair |
| title_fullStr | HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair |
| title_full_unstemmed | HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair |
| title_short | HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair |
| title_sort | hcn2 channel induced rescue of brain teratogenesis via local and long range bioelectric repair |
| topic | ion channel bioelectric teratogen nicotine non-local long-range |
| url | https://www.frontiersin.org/article/10.3389/fncel.2020.00136/full |
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