Ago1-KO Mouse

Ago1, or Argonaute 1, is a key protein in gene-silencing pathways mediated by small non-coding RNAs. It plays a pivotal role in various biological processes, such as plant growth and development, and is involved in microRNA-mediated regulation [2,3]. In animals, it has functions in areas like neurodevelopment, myogenic differentiation, and adipose tissue regulation, indicating its broad biological importance [1,4,5]. Genetic models, including those in Caenorhabditis elegans and mice, are valuable for studying Ago1 [6,7,8].

In mice, deletion of Ago1 in endothelial cells (EC-Ago1-KO) leads to an anti-obesity phenotype, with lower body weight, improved insulin sensitivity, and enhanced energy expenditure, via inhibition of thrombospondin-1 (THBS1/TSP1) [4]. In mouse embryonic stem cells, Ago1 depletion causes a redistribution of the repressive histone mark H3K9me3 and HP1α away from pericentromeric regions, and up-regulation of major satellite transcripts [7]. Also, Ago1 controls stemness in mouse embryonic stem cells through facilitating protein folding, independent of its small RNA-binding function [8]. In humans, de novo coding variants in Ago1 are associated with a neurodevelopmental disorder characterized by intellectual disability, speech and motor delay, and autistic behavior [1,9]. Modeling human Ago1 mutations in C. elegans shows disruptions in miRNA processing, miRISC formation, and target repression [6].

In summary, Ago1 is essential in multiple biological processes. Model-based research, especially using KO mouse models, has revealed its role in diseases like obesity-related metabolic disorders and neurodevelopmental disorders. These findings contribute to understanding the underlying molecular mechanisms and may provide insights for potential therapeutic strategies.

References:

1. Schalk, Audrey, Cousin, Margot A, Dsouza, Nikita R, Piton, Amelie, Gerard, Benedicte. 2021. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability. In Journal of medical genetics, 59, 965-975. doi:10.1136/jmedgenet-2021-107751. https://pubmed.ncbi.nlm.nih.gov/34930816/

2. Lemus, Tzitziki, Mason, Grace Alex, Bubb, Kerry L, Queitsch, Christine, Cuperus, Josh T. . AGO1 and HSP90 buffer different genetic variants in Arabidopsis thaliana. In Genetics, 223, . doi:10.1093/genetics/iyac163. https://pubmed.ncbi.nlm.nih.gov/36303325/

3. Martín-Merchán, Andrea, Lavatelli, Antonela, Engler, Camila, Rosano, Germán L, Bologna, Nicolas G. . Arabidopsis AGO1 N-terminal extension acts as an essential hub for PRMT5 interaction and post-translational modifications. In Nucleic acids research, 52, 8466-8482. doi:10.1093/nar/gkae387. https://pubmed.ncbi.nlm.nih.gov/38769059/

4. Tang, Xiaofang, Miao, Yifei, Luo, Yingjun, Zhong, Sheng, Chen, Zhen Bouman. 2020. Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction. In Circulation, 142, 365-379. doi:10.1161/CIRCULATIONAHA.119.041231. https://pubmed.ncbi.nlm.nih.gov/32393053/

5. Fallatah, Bodor, Shuaib, Muhammad, Adroub, Sabir, Lanzuolo, Chiara, Orlando, Valerio. . Ago1 controls myogenic differentiation by regulating eRNA-mediated CBP-guided epigenome reprogramming. In Cell reports, 37, 110066. doi:10.1016/j.celrep.2021.110066. https://pubmed.ncbi.nlm.nih.gov/34852230/

6. Duan, Ye, Li, Li, Panzade, Ganesh Prabhakar, Zinovyeva, Anna, Ambros, Victor. 2024. Modeling neurodevelopmental disorder-associated human AGO1 mutations in Caenorhabditis elegans Argonaute alg-1. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2308255121. doi:10.1073/pnas.2308255121. https://pubmed.ncbi.nlm.nih.gov/38412125/

7. Müller, Madlen, Fäh, Tara, Schaefer, Moritz, Ngondo, Richard Patryk, Ciaudo, Constance. 2022. AGO1 regulates pericentromeric regions in mouse embryonic stem cells. In Life science alliance, 5, . doi:10.26508/lsa.202101277. https://pubmed.ncbi.nlm.nih.gov/35236760/

8. Liu, Qiuying, Pepin, Rachel M, Novak, Mariah K, Worner, Kailey, Hu, Wenqian. 2024. AGO1 controls protein folding in mouse embryonic stem cell fate decisions. In Developmental cell, 59, 979-990.e5. doi:10.1016/j.devcel.2024.02.006. https://pubmed.ncbi.nlm.nih.gov/38458189/

9. Niu, Yue, Qian, Qiaoqiao, Li, Juan, Long, Lili, Yang, Zhixian. 2022. De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype. In Clinical genetics, 101, 459-465. doi:10.1111/cge.14114. https://pubmed.ncbi.nlm.nih.gov/35060114/