Modeling neurodevelopmental disorder-associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1

Author:

Duan Ye12ORCID,Li Li3,Panzade Ganesh Prabhakar3,Piton Amélie4,Zinovyeva Anna3ORCID,Ambros Victor1ORCID

Affiliation:

1. Program of Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605

2. Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Cambridge, MA 02138

3. Division of Biology, Kansas State University, Manhattan, KS 66506

4. Department of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology, Strasbourg University, CNRS UMR7104, INSERM U1258, Illkirch 67 400, France

Abstract

MicroRNAs (miRNA) associate with Argonaute (AGO) proteins and repress gene expression by base pairing to sequences in the 3′ untranslated regions of target genes. De novo coding variants in the human AGO genes AGO1 and AGO2 cause neurodevelopmental disorders (NDD) with intellectual disability, referred to as Argonaute syndromes. Most of the altered amino acids are conserved between the miRNA-associated AGO in Homo sapiens and Caenorhabditis elegans , suggesting that the human mutations could disrupt conserved functions in miRNA biogenesis or activity. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homologous gene , alg-1 . These alg-1 NDD mutations cause phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC (miRNA silencing complex) formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic, causing developmental and molecular phenotypes stronger than those of alg-1 null mutants, likely by sequestrating functional miRISC components into non-functional complexes. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or messenger RNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental AGO functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.

Funder

HHS | National Institutes of Health

Publisher

Proceedings of the National Academy of Sciences

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