Table 2. Proposed spinal muscular atrophy (SMA)-microRNA relationships.

miRNA	Role in MN disease	Targets	Organism/cell models and expression profiles	Findings and proposed mechanism of SMA pathogenesis	References
miR-2	Neuronal development and function; correct NMJ functioning	CHRM2, m2R	C. elegans model, SMA mouse model. Decreased	Alters NMJ function	(O'Hern et al., 2017)
miR-9 (1)	MN dendritic outgrowth and synaptic function	Neurofilament heavy subunit (NEFH), REST, Map1b, MCPIP1	Mouse, patient fibroblasts, patient serum. Decreased in spinal cord, but increased in skeletal muscle	Dysregulated expression in MNs differentiated from ESCs. Regulation of MN subtype determination (FOXP1). miR-9 can delay neurite outgrowth in vitro and impair radial neuronal migration in embryonic mouse neocortex in vivo.	(Catapano et al., 2016; Haramati et al., 2010)
miR-23a	Neuroprotective properties; regulate axonal development; suppress skeletal muscle atrophy	Atrogin1, MuRF1 (maybe, no direct target experiment was verified by luciferase assay)	Patient induced pluripotent stem cells, SMA mouse model. Decreased	miR-23a can prevent the astrocyte-conditioned media-induced MN loss in vitro. In mice model, enhanced miR-23a expression via virus vector increased MN soma size and muscle fiber area, and reduced NMJ defects	(Kaifer et al., 2019)
miR-100–5p	Abnormal proliferation of neural progenitors; aberrant cell cycle	Potentially insulin-like growth factor one receptor (IGF1R)	SMN∆7 mouse neural stem cells from spinal cord. Decreased	Decreased miR-100–5p in SMAΔ7 mice neural stem cells induces high IGF1R, excessive proliferation of neural progenitors, and prevents appropriate exit of the cell cycle.	(Luchetti et al., 2015)
miR-132 (possible)	Neuron dendritic outgrowth and synaptic plasticity; neovascularization, may cause ischemic pathology in both skeletal muscle and spinal cord of SMA model	Dysregulated expression due to TDP43 interaction with Dicer (amyotrophic lateral sclerosis data), p250GAP	SMA mice, patient serum. Decreased in spinal cord, but increased in skeletal muscle	Expression is dysregulated in TDP-43-deficient amyotrophic lateral sclerosis (ALS). Neuronal morphology and cognition in ALS. miR-132 can delay neurite outgrowth in vitro and impair radial neuronal migration in embryonic mouse neocortex in vivo. Involved in synaptic plasticity. Process of neovascularization. Recent reports have highlighted vascular defects in both skeletal muscle and spinal cord of SMA patients.	(Catapano et al., 2016)
miR-146	MN loss caused by astrocyte-mediated pathology through NFκB signaling	GDNF, NOTCH2, GATA transcription factors	Patient induced pluripotent stem cells. Increased	miR-146 levels are influenced both directly and indirectly by SMN1 levels. SMN re-expression decreases miR-146a levels nearly to control levels. The NFκB pathway is an inducer of miR-146a.	(Sison et al., 2017)
miR-183	Protein synthesis; axonal outgrowth	mTOR pathway	Mouse, cortical neurons, patient fibroblasts. Increased	Increased miR-183 and reduced local axonal translation of mTOR in SMN-deficient neurons.	(Kye et al., 2014)
miR-206 (2) (muscle-specific)	Myofiber formation; satellite cell differentiation; neuroprotective role in re-innervation of muscle endplates after acute nerve injury	Axis of HDAC4-FGFBP1, Pola1, BDNF	SMA mouse, patient serum. Increased in both spinal cord and skeletal muscle	Endogenously increased miR-206, with HDAC4 protein reduction and increased FGFBP1 mRNA, activates neuroprotective mechanism in muscle cells to increase re-innervation of muscle endplates.	(Catapano et al., 2016; Valsecchi et al., 2015)
miR-335–5p	Control of differentiation or self-renewal of mouse ESCs	MEST, OCT4, RB1	SMN∆7 mouse neural stem cells, human induced pluripotent stem cells. Decreased	Possible epigenetic regulation through methylation to affect cell differentiation.	(Luchetti et al., 2015; Murdocca et al., 2016)
miR-375	Neurogenesis and protects neurons from apoptosis in response to DNA damage.	P53, PAX6, CCND2	Human neural progenitor cell cultures. Decreased	MNs from an SMA patient have shown reduced levels of miR-375, elevated p53 protein levels, and higher susceptibility to DNA damage-induced apoptosis.	(Bhinge et al., 2016)
miR-431	Regulation of motor neuron axon neurite outgrowth	Chondrolectin (Chodl): a type one transmembrane protein and member of the c-type lectin domain-containing family	Mouse MN culture, patient fibroblasts/induced pluripotent stem cells. Increased	Increased miR-431 regulates motor neuron neurite length by targeting chondrolectin involved in motor neuron axon outgrowth.	(Wertz et al., 2016)

¹ miR-9/9* is another microRNA potentially implicated in motor neuron disease. It has been linked to the loss of spinal motor neurons that leads to SMA.

² Since miR-206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, this scenario probably accounts for its salutary effects in SMA.