Identification of a microRNA switch in spinal commissural axon guidance

Guo-fa Liu; Tao Yang

doi:10.4103/1673-5374.251300

摘要：The formation of neural circuits is governed by multiple classes of highly conserved extracellular guidance signals such as guidance cues, growth factors, and cell adhesion molecules (Kolodkin and Tessier-Lavigne, 2011; Stoeckli et al., 2018). During embryonic development, vertebrate commissural neurons project axons toward the floor plate and cross the midline of the spinal cord, a process relying upon the coordination of attractive and repulsive guidance cues (Kolodkin and Tessier-Lavigne, 2011; Stoeckli et al., 2018). For instance, floor plate-derived Sonic hedgehog (Shh) and Netrin-1 attract spinal cord commissural axons projecting toward the floor plate and crossing the midline, whereas Slit-mediated repulsion on precrossing commissural axons is silenced. In contrast, postcrossing commissural axons lose responsiveness to Netrin-1/Shh attraction, but acquire responsiveness to repulsion of Slits and Semaphorins (Stoeckli et al., 2018). It is believed that low level of Robo1, one of the Slit receptors, in precrossing commissural axons silence the responsiveness of commissural axons to Slit repulsion before midline crossing. However, Robo1 expression increases in postcrossing commissural axons, triggering Slit repulsion and simultaneously silencing Netrin-1-mediated attraction on commissural axon projection (Long et al., 2004). Although such a differential expression pattern of Robo1 acts as a molecular switch of Slit repulsion to control commissural axon guidance (Long et al., 2004), the molecular mechanisms underlying the fine-tuned regulation of temporal expression of Robo1 in developing commissural axons are still not well understood. MicroRNAs (miRNAs), non-coding small RNA transcripts (～22 nucleotides), bind to the 3′ untranslated region (3′UTR) of target mRNAs and regulate gene expression post-transcriptionally via mRNA decay and/or translational repression (Ambros and Chen, 2007). Emerging evidence indicate that miRNAs are involved in axon guidance by regulation of either guidance receptors at transcriptional level or their downstream signaling components at posttranscriptional level (Baudet et al., 2011; Zou et al., 2012; Bellon et al., 2017). However, a key question that remains unanswered is whether miRNAs could directly regulate Robo1 expression in the developing vertebrate spinal cord. Recently, one study from our lab has shown that miR-92, a highly conserved miRNA, may function as a molecular switch to specifically repress Robo1 expression, which further regulates Slit repulsion on precrossing commissural axons and plays an important role in commissural axon guidance in the developing chicken spinal cord (Yang et al., 2018). This finding provides a working model of the regulation of Robo1 expression in Slit-mediated commissural axon guidance in the vertebrate nervous system (Figure 1).