Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Jean and George Brumley, Jr. Neonatal-Perinatal Institute, Durham, NC 27710, USA.
Brain Imaging and Analysis Center, Duke University School of Medicine, Durham, NC 27710, USA.
Sci Signal. 2017 Oct 10;10(500):eaal4055. doi: 10.1126/scisignal.aal4055.
Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency-controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.
心脏和面部的先天缺陷很常见，大多数没有已知的遗传原因，这表明环境因素起了作用。母亲在怀孕早期发热是与这些缺陷相关的环境危险因素。神经嵴细胞是处于关键发育窗口的原始细胞群，对有风险的组织的发育至关重要。我们报告称，在心脏和面部发育的关键窗口期，两种热激活瞬时受体电位 (TRP) 离子通道 TRPV1 和 TRPV4 存在于神经嵴细胞中。TRPV1 拮抗剂可预防发热诱导的鸡胚缺陷的发生。TRPV1 或 TRPV4 的化学激动剂处理复制了发热诱导的鸡胚和斑马鱼胚胎的先天缺陷。为了测试神经嵴细胞中瞬时 TRPV 通道通透性是否足以诱导这些缺陷，我们设计了铁结合修饰的 TRPV1 和 TRPV4，使这些通道能够在特定的细胞位置和特定的发育时间在鸡胚中，通过射频电磁场进行远程和非侵入性激活。短暂刺激射频控制的 TRP 通道在神经嵴细胞中复制了与发热相关的鸡胚发育缺陷。我们的数据提供了一种以前未描述的先天性缺陷机制，即发热激活了负性影响胎儿发育的离子通道。
