Growth Cone Tctp Is Dynamically Regulated by Guidance Cues

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.

Dysregulation of TCTP in Biological Processes and Diseases

“…The importance of TCTP for organ development was supported by a new report showing that TCTP promotes liver regeneration via mTORC2/Akt signalling [16], by studies on axon guidance [17][18][19] and on brain development [20]. Roque et al demonstrated the role of TCTP for axon guidance and development in the visual system of Xenopus laevis [18] and the importance of its localised translational regulation in axonal growth cones [17].…”

“…They showed that it is indeed a protein essential for the normal development of the visual circuitry in the frog [18]. In a follow-up paper, the authors specifically investigated the translational regulation of TCTP and its importance for axon guidance [17]. They demonstrated that in axons of retinal ganglion cells, local TCTP synthesis is regulated by two axon guidance cues in an mTORC1-dependent fashion.…”

“…Therefore, the biological importance of the second isoform is still elusive. In addition, for the regulation of TCTP expression in the axonal growth cone, it was shown that it is the shorter isoform, which is subject to translational regulation [17]. The first example of regulation of TCTP expression via the 3 -UTR of its mRNA was revealed in a recent, very interesting report [66].…”

Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

“…During axon pathfinding and branching, axons encounter multiple cues, such as EphrinB2 and Netrin-1,and can integrate these cues by forming a complex between their respective receptors in a ligand-dependent manner (Morales and Kania, 2017; Dudanova and Klein, 2013; Poliak et al, 2015). The cue EphrinA1 has been reported to decrease local translation in hippocampal axons (Nie et al, 2010) and the rapid local translation of the Translationally controlled tumor protein (Tctp), which is up-regulated by Netrin-1 (Gouveia Roque and Holt, 2018). Therefore, we asked whether co-stimulation with EphrinA1 and Netrin-1 alters the dissociation of ribosomes from DCC.…”

Investigating the Role of Translationally Control Tumor Protein in Growth, Development and Differentiation of Dictyostelium discoideum

“…Also, knockdown of TCTP in Drosophila results in reduced cell number and organ size causing the larvae to die by first-instar stage (Hsu et al, 2007). High abundance of TCTP transcript is found in retinal ganglion cell and adult axons indicate TCTP regulates the growth of retinal ganglion cell axons (Roque and Holt, 2018). It is associated with the survival machinery of axons and has role in the development of vertebrate neural circuit (Roque et al, 2016).…”