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

被引：19

作者：

Amin, Neal D. ^{[1
,2
]}

Senturk, Gokhan ^{[1
]}

Costaguta, Giancarlo ^{[1
]}

Driscoll, Shawn ^{[1
]}

O'Leary, Brendan ^{[1
]}

Bonanomi, Dario ^{[1
,3
]}

Pfaff, Samuel L. ^{[1
]}

机构：

[1] Salk Inst Biol Studies, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA

[3] Ist Sci San Raffaele, Div Neurosci, Via Olgettina 60, I-20132 Milan, Italy

来源：

NEURON | 2021年 / 109卷 / 20期

基金：

美国国家卫生研究院;

关键词：

MICRORNA; EXPRESSION; RNA; MUTATIONS; DYSREGULATION; TRANSCRIPTION; BIOGENESIS; DIVERSITY; PROVIDES; DISEASE;

D O I：

10.1016/j.neuron.2021.07.028

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：3252 / +

页数：23