The Mexican axolotl salamander serves as a unique model system for studying regeneration, owing to its ability to faithfully restore its spinal cord following injury. This process relies on a population of neural stem cells (NSCs) capable of differentiating into new glia and neurons. Now, Karen Echeverri and co-workers investigate the function of miR-200a, a known pro-regenerative microRNA, in this process. Using RNA sequencing on injured spinal cord tissue, they show that the transcription factor and mesodermal marker brachyury is strongly upregulated upon miR-200a inhibition. When miR-200a is inhibited, the proportion of NSCs in uninjured and injured tissues increases, while the number of newborn neurons decreases. Instead, muscle fibres form upon miR-200a inhibition, suggesting that brachyury upregulation promotes differentiation towards a mesodermal fate. The authors demonstrate that, on a molecular level, brachyury upregulation upon miR-200a inhibition may be the result of increased FGF and Wnt signalling. Specifically, miR-200a directly represses expression of β-catenin, the key signal transducer of Wnt signalling. Together, these findings establish that, by regulating the FGF and Wnt signalling pathways, miR-200a represses mesodermal cell fate decisions upon spinal cord injury in axolotl to specifically promote the replacement of neurons and glia.
