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Front Cell Neurosci 2020 May 26;14:136. doi: 10.3389/fncel.2020.00136.
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HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair.

Pai VP , Cervera J , Mafe S , Willocq V , Lederer EK , Levin M .

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.

PubMed ID: 32528251
PMC ID: PMC7264377
Article link: Front Cell Neurosci
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ddx59 foxg1 hcn2 otx2

Phenotypes: Xla.wt + nicotine (Fig. 1 F r1c2) [+]

Article Images: [+] show captions
References [+] :
Acampora, Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. 1995, Pubmed