Abstract
Translationally controlled tumor protein (Tctp) contributes to retinal circuitry formation by promoting axon growth and guidance, but it remains unknown to what extent axonal Tctp specifically influences axon development programs. Various genome-wide profiling studies have ranked tctp transcripts among the most enriched in the axonal compartment of distinct neuronal populations, including embryonic retinal ganglion cells (RGCs), suggesting its expression can be regulated locally and that this may be important during development. Here, we report that growth cone Tctp levels change rapidly in response to Netrin-1 and Ephrin-A1, two guidance cues encountered by navigating RGC growth cones. This regulation is opposite in effect, as we observed protein synthesis- and mTORC1-dependent increases in growth cone Tctp levels after acute treatment with Netrin-1, but a decline upon exposure to Ephrin-A1, an inhibitor of mTORC1. Live imaging with translation reporters further showed that Netrin-1-induced synthesis of Tctp in growth cones is driven by a short 3′untranslated region (3′UTR) tctp mRNA isoform. However, acute inhibition of de novo Tctp synthesis in axons did not perturb the advance of retinal projections through the optic tract in vivo, indicating that locally produced Tctp is not necessary for normal axon growth and guidance.
Highlights
Axon guidance is informed by successive molecular signposts—guidance cues—in the embryonic nervous system that are continuously integrated by the growth cone, a sensory structure at the tip of developing axons
We asked whether interfering pharmacologically with the protein translation machinery blocked the observed upregulation of growth cone translationally controlled tumor protein (Tctp) expression triggered by Netrin-1
Both CHX, an inhibitor of translation elongation, and rapamycin, an allosteric mTORC inhibitor, prevented the increase in Tctp signal when applied acutely just before the Netrin-1 stimulus (Figures 1A,B and Supplementary Figure S1A). These results reveal that Tctp levels in the growth cone are rapidly regulated by Netrin-1, and that this is a protein synthesis- and mTORC1-dependent event
Summary
Axon guidance is informed by successive molecular signposts—guidance cues—in the embryonic nervous system that are continuously integrated by the growth cone, a sensory structure at the tip of developing axons. Studies spanning the past three decades have revealed that a certain degree of functional autonomy is held by this cellular outpost, perhaps best illustrated by the demonstration that axons separated from their cell bodies can still navigate correctly in vivo (Harris et al, 1987). This operational independence is, understandably, essential for pathfinding growth cones to respond rapidly and precisely to their ever-changing environment. A combination of central nervous system-wide knockdown approaches revealed that Tctp regulates axonal growth and guidance, and leads to compromised mitochondrial operation in axons
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