Figure 3.

The interplay of RNA modification and local translation for neuronal wiring (A) Regulation of local translation of Gap43 mRNA for axon elongation. FTO mRNA is locally translated in axons. The eraser FTO mediates the de-methylation of Gap43^m6A mRNA in axons. This leads to local translation of Gap43 mRNA. Via an alternative pathway, HSRP binds to the 3′UTR of Gap43 mRNA to repress its translation. The non-coding RNA ALAE is enriched in the axon and sequesters HSRP. Released Gap43 mRNA can then be translated locally. Gap43 associates with the plasma membrane and regulates actin dynamics to promote axon elongation. The question mark on the dotted line highlights that it is unknown whether these two pathways interact. (B) RNA metabolism of Robo3 involved in midline crossing of commissural neurons. (Top) Cross-section of spinal cord showing the trajectory of commissural neurons. During development, these neurons project their axons ventrally, where they cross the midline to target the contralateral side. (Bottom) Robo3 RNA metabolism leads to spatially and temporally controlled expression of Robo3 during navigation of commissural axons. (Left) Events occurring in the soma. (Right) events occurring in the axons. Robo3 can produce 2 isoforms via AS, Robo3.1 and Robo3.2. From these isoforms, Robo3.1 is methylated, and the m⁶A modification is read by YTHDF1, which stimulates translation of Robo3.1^m6A in the soma. When commissural axons reach the floor plate, signaling from the floor plate downregulates YTHDF1 expression, thus inhibiting Robo3.1 expression in post-crossing axons. At this point, floor plate signaling induces the local translation of the Robo3.2 isoform. After translation, Robo3.2 is degraded by nonsense-mediated decay. Growth cones projecting to the floor plate express Robo3.1 only. After reaching the floor plate, the protein levels of Robo3.1 decrease and Robo3.2 protein levels increase. Shortly after crossing the midline, Robo3.2 protein levels are downregulated.