Mechanisms of brain wiring by axonal miRNAs: miR-181 and miR-182

Abstract

The highly complex nervous system is built upon an intricate network of neurons. In order to make a functional network, the establishment of precise connections is crucial. Neuronal networks are established early during development when neurons send out axons that navigate through complex environments to connect to their target. Chemotropic attractant or repellent cues, cell adhesion molecules, morphogens and a wide range of factors secreted or expressed by guidepost cells enable axon guidance. The leading tip of the axon, the GC is important to sense the environment and integrate extracellular signals to navigate precisely. The axonal GC has a large repertoire of mRNAs that are dynamic in nature. Local regulation of transcripts in navigating axons is suspected to ensure precise pathfinding. However, mechanisms involving regulation of expression of these transcripts within GCs are largely unknown. This thesis investigates whether microRNAs, one of the quintessential posttranscriptional regulators, can regulate axon guidance by fine-tuning mRNA expression within subcellular compartments. To explore microRNA roles in axon guidance, Xenopus laevis visual system was used as a model. Profiling axons of retinal ganglion cells revealed the presence of miRNAs within axons. The most abundant axonal miRNAs, the miR-181 family and miR-182, exhibit distinct roles in regulating axon guidance in vivo. Loss of function analyses suggests that both miRNA families are required for accurate axonal targeting but involve different mechanisms. Thus, specific axonal microRNAs locally regulate mRNAs contributing to error-free pathfinding.