MicroRNA‐181a Mediates Neuronal Differentiation and Modulates Microtubule Stability.

Stroke remains among the top causes of death and is the leading cause of persisting neurological disability in the United States. Treatment options remain limited to early reperfusion with thrombolysis or clot retrieval, and therapies capable of repairing damage resulting from ischemic insult are needed. Microtubules (MTs) have been recently recognized as a potential target for post‐injury therapy in the central nervous system. MTs consist of a stable and labile domain, which differ in their resistance to depolymerization, and by modulating intrinsic mechanisms that work to regulate the proportions of stable and labile MT mass in the axon, we can restore MT integrity after injury. MicroRNAs (miRNAs) are ~22‐nucleotide RNAs that regulate gene expression. MicroRNA‐181a (miR‐181a) is enriched in astrocytes, critical regulators of neuronal homeostasis and neurogenesis. Mir‐181a increases in the brain after stroke, and inhibition of miR‐181a improves functional outcomes in animal models. Using primary neuronal stem cell cultures, we demonstrate here that miR‐181a regulates neuronal differentiation. In situ analysis identified miR‐181a as a likely regulator of MT dynamics through the modulation of the MAPT (tau), MAP1B, and FIGN (fidgetin) genes. MAPT (Tau) and MAP1B are microtubule‐associated proteins (MAPs) that have been demonstrated to contribute to MT stability and neurogenesis, while fidgetin is a severing protein thought to target the labile domain of MTs and modulates a cell's ability to migrate and regulates neuronal elaboration. Therefore, we tested the hypothesis that modulation of miR‐181a activity alters MT integrity in primary neuron and astrocyte cultures and N2a cell line cultures. Immunostaining and biochemical analyses revealed injury and miR‐181a dependent changes to MAPs implicated in the modulation of microtubule stability. Overall, these results demonstrate that microRNAs can be a novel and effective target for restoring MT stability after ischemic brain injury, as well as advancing our understanding of the contributions of astrocyte regulation to increase neurogenesis and post‐injury repair after stroke.Support or Funding InformationAmerican Heart Association Fellow to Faculty Transition award: No. 14FTF19970029This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.