Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.

Abstract

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1126/scisignal.aal4055

Publication Info

Hutson, Mary R, Anna L Keyte, Miriam Hernández-Morales, Eric Gibbs, Zachary A Kupchinsky, Ioannis Argyridis, Kyle N Erwin, Kelly Pegram, et al. (2017). Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects. Science signaling, 10(500). p. eaal4055. 10.1126/scisignal.aal4055 Retrieved from https://hdl.handle.net/10161/30122.

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Scholars@Duke

Rosenberg

Paul Brian Rosenberg

Professor of Medicine
Benner

Eric James Benner

George W. Brumley, Jr. M.D Assistant Professor

As a neonatologist, my research interests revolve around improving the survival and quality of life of high-risk neonates cared for in Neonatal Intensive Care Units. My primary interest is perinatal brain injuries impacting both full-term infants and those born prematurely.  One of the most common forms of perinatal brain injury involves damage to white matter (myelin). My laboratory has developed models of perinatal brain injury to investigate how the endogenous neural stem cell responds to myelin injury. Our hope is to develop innovative strategies to successfully redirect stem cells into the oligodendrocyte lineage and promote myelination after injury.  In order to successfully restore myelination after injury, we want to better understand the molecular mechanisms governing 2 important aspects of myelin development. 

First, we must understand the molecular signals that drive neural stem cells to differentiate into oligodendrocytes (oligodendrogenesis) and how brain injury impacts this process. This interest has led my laboratory to investigate intracellular and extracellular changes that occur in the neural stem cell niche following injuries that lead to white matter damage. 

Secondly, after stem cell commitment to the oligodendrocyte lineage has occurred, we must understand the ongoing signals from the neural environment that influence oligodendrocyte maturation. For this work, my laboratory has developed an innovative technology to remotely control ion channels non-invasively using magnetic fields. Using this technology, we are developing strategies to alter the activity of targeted neural circuits both in utero as well as postnatally to understand the impact of altered activity on myelin maturation. Members of my laboratory are also currently using this technology to understand how altered temperature-gated channel activity in utero may contribute to birth defects associated with maternal fevers. 


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