MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish

Abstract

MicroRNAs (miRNAs) play important roles during development and also in adult organisms by regulating the expression of multiple target genes. Here, we studied the function of miR-133b during zebrafish spinal cord regeneration and show upregulation of miR-133b expression in regenerating neurons of the brainstem after transection of the spinal cord. miR-133b has been shown to promote tissue regeneration in other tissue, but its ability to do so in the nervous system has yet to be tested. Inhibition of miR-133b expression by anti-sense morpholino (MO) application resulted in impaired locomotor recovery and reduced regeneration of axons from neurons in the NMLF (nucleus of the medial longitudinal fascicle), SRF (superior reticular formation), and IMRF (intermediate reticular formation). miR-133b targets the small GTPase RhoA, which is an inhibitor of axonal growth, as well as other neurite outgrowth-related molecules. Our results indicate that miR-133b is an important determinant in spinal cord regeneration of adult zebrafish through reduction of RhoA protein levels by direct interaction with its mRNA. While RhoA has been studied as a therapeutic target in spinal cord injury, this is the first demonstration of endogenous regulation of RhoA by a microRNA that is required for spinal cord regeneration in zebrafish. The ability of miR-133b to suppress molecules that inhibit axon regrowth may underlie the capacity for adult zebrafish to recover locomotor function after spinal cord injury (SCI).

microRNA-99a Reduces Lipopolysaccharide-Induced Oxidative Injury by Activating Notch Pathway in H9c2 Cells

“…40,41) Some miRNAs could have an impact on these apoptotic factors to regulate cell apoptosis. 42,43) In our study, miR-99a was capable of promoting BCL2 and suppressing the activation of caspase 3, supporting that miR-99a inhibits cell apoptosis in LPS-treated H9c2 cells. This result also implies that miR-99a regulates these apoptotic factors, and that more detailed mechanisms may be uncovered in further research.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…In normal developed fins, high levels of miR133 are maintained, accompanied by a cessation of Fgf signalling, indicating that high miR133 levels normally suppresses tissue proliferation factors and signalling pathways, maintaining deve loped tissue homeostasis [68] . Increased miR133b also influences spinal cord regeneration in adult zebrafish, reducing the level of RhoA protein, an inhibitor of axonal growth, and stimulating spinal cord regeneration of axons from neurons in particular brain structures [69] .…”

MiR-133b Promotes Neurite Outgrowth by Targeting RhoA Expression

“…[9] In CNS, miR-133b is enriched in the midbrain and plays an important role in differentiation and degeneration of midbrain dopaminergic neurons through repressing Pitx3, a paired-like homeodomain transcription factor [10,11]. Moreover, recent studies showed that miR-133b was implicated in the functional recovery of spinal cord injury and stroke [12,13,14], while the cellular role of miR-133b in neurite outgrowth of neural cells remained unclear.…”