| First Author | Amin ND | Year | 2021 |
| Journal | Neuron | Volume | 109 |
| Issue | 20 | Pages | 3252-3267.e6 |
| PubMed ID | 34450025 | Mgi Jnum | J:315141 |
| Mgi Id | MGI:6830543 | Doi | 10.1016/j.neuron.2021.07.028 |
| Citation | Amin ND, et al. (2021) A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose. Neuron 109(20):3252-3267.e6 |
| abstractText | Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA's in vivo abundance (rather than its binary gain or loss) are not well understood. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-selective gene regulator associated with motor neuron disease. Titration of miR-218 cellular dose unexpectedly revealed complex, non-ratiometric target mRNA dose responses and distinct gene network outputs. A non-linearly responsive regulon exhibited a steep miR-218 dose-dependent threshold in repression that, when crossed, resulted in severe motor neuron synaptic failure and death. This work demonstrates that a miRNA can govern distinct gene network outputs at different expression levels and that miRNA-dependent phenotypes emerge at particular dose ranges because of hidden regulatory inflection points of their underlying gene networks. |
