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

Michael Kiebler

Michael Kiebler

Michael Kiebler

Rico Schieweck

Rico Schieweck

Rico Schieweck

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Active translation is generally assumed to occur typically on polysomes, consisting of mRNAs occupied by two or more elongating ribosomes. Monosomes – a mix of mRNAs bound by a single ribosome – in contrast, were thought to represent mainly initiating ribosomes.

This “dogma”, however, has been recently challenged by Heyer and Moore {1} a topic that has received significant attention lately. Particularly in subcellular compartments of a cell, where polysomes appear to be rare but where local translation takes place, it was tempting to speculate that monosomes might critically contribute to the translatome. Needless to say, this interesting and exciting hypothesis is challenging to address experimentally.

Therefore, Heyer and Moore {1} decided to exploit a combinatorial approach consisting of density gradient fractionation and ribosome profiling in yeast. In this outstanding and very convincing study, the authors provide strong experimental evidence that the vast majority of monosomes are in the process of elongation, not initiation. This allowed them to formulate an important working hypothesis: mRNAs with long open reading frames (ORFs) and high rates of initiation will be preferentially translated on polysomes, and mRNAs with short ORFs and slow rates of initiation are occupied by monosomes. 

This interesting new finding was further substantiated by two additional studies. Recently published findings by Koppers et al. suggest that elongating monosomes might also exist in axonal growth cones. Please check out the stunning EM of axonal growth cones showing ribosomes aligned in a row under the plasma membrane, (see their Fig. 3F). Moreover, Biever et al. {2} provided further experimental evidence that monosomes actively translate mRNAs in neuronal processes. Please see our separate recommendations on both of the papers referenced {1-2}.

In conclusion, these findings raise the question of what makes an mRNA preferring monosomes rather than polysomes for translation? Which features or RNA-binding proteins control this decision? The three mentioned studies clearly provide exciting new insight into the dynamics of translation. Moreover, they redefine our view on translation which is far too complex to be subdivided into initiation, elongation and termination. 
 

Stephanie Gupton

Stephanie Gupton

Stephanie Gupton

Shalini Menon

Shalini Menon

Shalini Menon

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Establishing proper neuronal circuitry is a highly complex process and encompasses the extension of neuronal axons toward synaptic partners. Axons are guided by numerous attractive or repulsive extracellular cues that are perceived by specific cognate receptors present on axonal growth cones. The guidance cue-receptor interactions then induce signaling cascades followed by the cytoskeletal reorganization required to steer the axon. These responses are often rapid, happening on the order of minutes, and are facilitated by local protein translation in the growth cone. The locally translated proteome is specified by the ligand-receptor interaction and influences axonal responses.

Cellular mechanisms that regulate local translation include mRNA modification, regulation of microRNAs, posttranslational modification of ribosomal binding proteins and translation factors, and receptor-ribosome coupling. The receptor-ribosome coupling theory to induce local protein translation in response to an external guidance cue was demonstrated by Tcherkezian et al {1}. Using murine commissural axon growth cones and HEK 293 cells, theirs study demonstrated that the netrin-1 receptor DCC associated with the ribosomal translation machinery, and when stimulated with netrin-1, the machinery dissociated from DCC, resulting in rapid translation of a specific subset of proteins required for appropriate growth cone response.

However, whether this mechanism occurred in multiple neuronal cell types and was utilized by other ligand-receptor pairs was not well understood. In this elegant study, Koppers et al, using Xenopus retinal ganglion cells and a human neuronal cell line, SH-SY5Y, demonstrated that receptor-ribosome coupling was used by the guidance receptors DCC and neuropilin-1 (Nrp1).

Their results suggested that a distinct subset of RBPs bound each receptor. These RBPs were bound to specific mRNAs, which recruited ribosomes to the receptors. They found that ribosomes dissociated from receptors in the presence of the receptor-ligand. However, co-stimulation with multiple ligands altered the dissociation of ribosomes. For example, stimulation with netrin-1 and ephrin1A, prevented dissociation of DCC specific ribosomal protein RPL5/uL18 from DCC. Additionally, they demonstrated that receptor endocytosis was critical for ribosomal dissociation from the receptor.

In conclusion, their research suggests that receptor-ribosome coupling is widely used across multiple guidance cue receptors and in many different neuronal cell types. They provide a mechanism by which receptor-ribosome coupling, and then uncoupling following stimulation by a guidance cue, leads to the translation of a subset of mRNAs specific to the receptor changes the local proteome rapidly for a cue-specific axonal response.