Clark, C., Austen, O., Poparic, I., and Guthrie, S. (2013) alpha2-Chimaerin Regulates a Key Axon Guidance Transition during Development of the Oculomotor Projection. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(42):16540-16551.
The 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 α2-chimaerin signaling molecule. We have used the zebrafish to model the role of α2-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 α2-chimaerin in this guidance process and found that axons expressing gain-of-function α2-chimaerin
isoforms failed to undergo the 52 hpf transition in filopodial dynamics, leading to axon stalling. α2-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 α2-chimaerin signaling is required
for key oculomotor axon guidance decisions, and provide a zebrafish model for Duane Retraction Syndrome.