A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose.
Neuron
; 109(20): 3252-3267.e6, 2021 10 20.
Article
em En
| MEDLINE
| ID: mdl-34450025
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença dos Neurônios Motores
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Dosagem de Genes
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MicroRNAs
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Redes Reguladoras de Genes
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Neurônios Motores
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article