期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 14, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2020.00136
关键词
ion channel; bioelectric; teratogen; nicotine; non-local; long-range; regenerative medicine
资金
- Allen Discovery Center program through The Paul G. Allen Frontiers Group [12171]
- Templeton World Charity Foundation [TWCF0089/AB55]
- National Institutes of Health [AR055993-01, AR061988]
- Ministerio de Ciencia, Innovacion y Universidades (Spain)
- European Regional Development Funds (FEDER) [PGC2018-097359-B-I00]
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.
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