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a2-chimaerin regulates a key axon guidance transition during development of the oculomotor projection
journal contribution
posted on 2023-06-09, 06:13 authored by Christopher Clark, Oliver Austen, Ivana Poparic, Sarah GuthrieSarah GuthrieThe ocular motor system consists of three nerves which innervate six muscles to control eye movements. In humans, defective development of this system leads to eye movement disorders, such as Duane Retraction Syndrome, which can result from mutations in the a2-chimaerin signaling molecule. We have used the zebrafish to model the role of a2-chimaerin during development of the ocular motor system. We first mapped ocular motor spatiotemporal development, which occurs between 24 and 72 h postfertilization (hpf), with the oculomotor nerve following an invariant sequence of growth and branching to its muscle targets. We identified 52 hpf as a key axon guidance “transition,” when oculomotor axons reach the orbit and select their muscle targets. Live imaging and quantitation showed that, at 52 hpf, axons undergo a switch in behavior, with striking changes in the dynamics of filopodia. We tested the role of a2-chimaerin in this guidance process and found that axons expressing gain-of-function a2-chimaerin isoforms failed to undergo the 52 hpf transition in filopodial dynamics, leading to axon stalling. a2-chimaerin loss of function led to ecotopic and misguided branching and hypoplasia of oculomotor axons; embryos had defective eye movements as measured by the optokinetic reflex. Manipulation of chimaerin signaling in oculomotor neurons in vitro led to changes in microtubule stability. These findings demonstrate that a correct level of a2-chimaerin signaling is required for key oculomotor axon guidance decisions, and provide a zebrafish model for Duane Retraction Syndrome.
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Publication status
- Published
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- Published version
Journal
Journal of NeuroscienceISSN
0270-6474Publisher
Society for NeuroscienceExternal DOI
Issue
42Volume
33Page range
16540-16551Department affiliated with
- Neuroscience Publications
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- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-05-10First Open Access (FOA) Date
2017-05-10First Compliant Deposit (FCD) Date
2017-05-10Usage metrics
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