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Functional canonical RNAi in mice expressing a truncated Dicer isoform and long dsRNA

V. Buccheri, J. Pasulka, R. Malik, Z. Loubalova, E. Taborska, F. Horvat, MI. Roos Kulmann, I. Jenickova, J. Prochazka, R. Sedlacek, P. Svoboda

. 2024 ; 25 (7) : 2896-2913. [pub] 20240520

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019904

Grantová podpora
20-03950X Czech Science Foundation
647403 EC | European Research Council (ERC)
LO1419 Ministry of Education, Youth, and Sports of the Czech Republic
LM2018126 Ministry of Education, Youth, and Sports of the Czech Republic
LM2023036 Ministry of Education, Youth, and Sports of the Czech Republic
LM2023050 Ministry of Education, Youth, and Sports of the Czech Republic
90254 Ministry of Education, Youth, and Sports of the Czech Republic
90255 Ministry of Education, Youth, and Sports of the Czech Republic
PhD fellowship Charles University
RVO 68378050 Czech Academy of Sciences

Canonical RNA interference (RNAi) is sequence-specific mRNA degradation guided by small interfering RNAs (siRNAs) made by RNase III Dicer from long double-stranded RNA (dsRNA). RNAi roles include gene regulation, antiviral immunity or defense against transposable elements. In mammals, RNAi is constrained by Dicer's adaptation to produce another small RNA class-microRNAs. However, a truncated Dicer isoform (ΔHEL1) supporting RNAi exists in mouse oocytes. A homozygous mutation to express only the truncated ΔHEL1 variant causes dysregulation of microRNAs and perinatal lethality in mice. Here, we report the phenotype and canonical RNAi activity in DicerΔHEL1/wt mice, which are viable, show minimal miRNome changes, but their endogenous siRNA levels are an order of magnitude higher. We show that siRNA production in vivo is limited by available dsRNA, but not by Protein kinase R, a dsRNA sensor of innate immunity. dsRNA expression from a transgene yields sufficient siRNA levels to induce efficient RNAi in heart and muscle. DicerΔHEL1/wt mice with enhanced canonical RNAi offer a platform for examining potential and limits of mammalian RNAi in vivo.

Citace poskytuje Crossref.org

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