Details

Autor(en) / Beteiligte

• Amin, Neal D.
• Senturk, Gokhan
• Costaguta, Giancarlo
• Driscoll, Shawn
• O’Leary, Brendan
• Bonanomi, Dario
• Pfaff, Samuel L.

Titel

A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose

Ist Teil von

• Neuron (Cambridge, Mass.), 2021-10, Vol.109 (20), p.3252-3267.e6

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •miRNA cellular dose is a major determinant of in vivo neuronal mRNA target selection•Modulation of miR-218 levels reveals distinct dose-response curves of target mRNAs•Motor failure occurs at the miR-218 dose inflection point for an exponential regulon•Motor neuron subtypes are distinguished by magnitude of miR-218-mediated effects By genetically titrating the levels of the ALS-associated miR-218 in mice, Amin et al. reveal an in vivo inflection point in target mRNA repression that underlies a phenotypic threshold for neuromotor defects and survival.