The travels of mRNAs in neurons: do they know where they are going?

Abstract

Neurons are highly polarized cells that can extend processes far from the cell body. As such, transport of messenger RNAs serves as a set of blueprints for the synthesis of specific proteins at distal sites. RNA localization to dendrites and axons confers the ability to regulate translation with extraordinary precision in space and time. Although the rationale for RNA localization is quite compelling, it is unclear how a neuron orchestrates such a complex task of distributing over a thousand different mRNAs to their respective subcellular compartments. Recent single-molecule imaging studies have led to insights into the kinetics of individual mRNAs. We can now peer into the transport dynamics of mRNAs in both dendrites and axons.

Figure 1.

Snapshot of mRNA transport in neuronal processes. In both dendrites and axons, mRNPs (complexes of mRNAs with RBPs) are actively transported along MT tracks (minus-ends depicted as boxes). The MT are of mixed orientation in proximal dendrites and more uniform polarity in distal dendrites or axons. The oscillatory behavior of actively transported mRNAs is depicted with the arrows indicating the possible movement directions, anterograde in green versus retrograde in red. The mRNPs traveling in axons and dendrites share common features and the inset shows a magnified view of an mRNP associated with the motors dynein and kinesin. Different ratios of the motors associated with the mRNP represent the ‘tug of war’ scenario where the movement is determined by the net combined force. In dendrites, mRNAs can be localized along the entire length of the dendrite often near the base of a stimulated dendritic spine. For axons, the final destination is the growth cone, where the mRNAs undergo corralled diffusion.

Figure 2.

Model of mRNA localization in dendrites following local synaptic stimulation. (A) Dendritic mRNPs (exemplified by β-actin) can exhibit a scanning behavior like a circling conveyor belt referred to as the ‘sushi belt model’. (B) Following stimulation, these mRNPs localize to the activated spines with high efficiency. This represents the ‘synaptic tagging and capture’ scenario where β-actin mRNAs are specifically anchored near activated synapses, and undergo local translation to generate a pool of new β-actin proteins which can be incorporated into the expanding dendritic spine structure. This model of structural plasticity underscores the importance of mRNAs localization and local translation. The exact mechanism of how the capture occurs, such as the presence and the role of an anchoring protein (i.e. ZBP1/IGF2BP1) in localization and persistence of the mRNA at the designated dendritic spine needs further elucidation.

Figure Box1:

mRNP trajectory analysis methods, as adapted from Monnier et al. Nature Methods 2015 [48]. (A) Snapshot from live imaging of MS2-tagged β-actin mRNAs in dendrites. Particle trajectory of a single mRNP and its kymograph. (B) Analysis of the mRNP trajectory with a diffusive-only HMM approach versus HMM-Bayes approach, which accounts for both diffusive state (D, blue) and active transport state (DV, pink). The states are annotated along the entire trajectory with the time spent in each state.