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Neurodevelopmental miR-135a-1-3p and miR-135b-3p promote long-distance axon regeneration after injury in the central visual pathway

ABSTRACT: Micro-RNAs (miRNAs) play roles in the mammalian central nervous system (CNS) development and disease but the functions of specific miRNA families’ members in defined neuronal types are poorly understood. Here, we characterized the miR-135 family members in the mouse CNS retinal ganglion cell (RGC) and cortical projection neurons development, and tested whether reverting expression towards embryonic levels for the identified developmentally-regulated miR-135 family members may reactivate the intrinsic axon growth capacity following axonal injury in the adult CNS. We found that, two-out-of-five miR-135 family members, miR-135a-1-3p and miR-135b-3p, were developmentally-downregulated, with further downregulation after axonal injury, in neurons. Importantly, RGC-targeted mimics of miR-135a-1-3p and miR-135b-3p promoted neuroprotection and axon regeneration following optic nerve injury, with axons regrowing through a segment of the central visual pathway when co-treated with axon growth-supporting small fibronectin-based recombinant protein. Finally, transcriptomic profiling of the treated RGCs showed that genes involved in neurodevelopment/neuroprotection were embedded in the gene networks affected by the treatments. Thus, miR-135a-1-3p and miR-135b-3p are developmentally-downregulated in the mammalian CNS projection neurons and present options for translation towards CNS injury treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE337069 | GEO | 2026/09/02

REPOSITORIES: GEO

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Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.

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Neurodevelopmental miR-135a-1-3p and miR-135b-3p promote long-distance axon regeneration after injury in the central visual pathway

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