Muscle pathophysiology in AGO1 and AGO2 genetic disorders

The recruited doctoral fellow (DF01) will investigate the molecular and cellular mechanisms by which pathogenic variants in AGO1 and AGO2 disrupt skeletal muscle development and function. Argonaute proteins are core components of the RNA-induced silencing complex (RISC) and essential mediators of microRNA (miRNA)-dependent gene regulation. Beyond their canonical role in post-transcriptional gene silencing, AGO proteins participate in transcriptional regulation, mRNA stability control, and alternative splicing, contributing broadly to the fine-tuning of developmental gene expression programs.

Heterozygous pathogenic variants in AGO1 and AGO2 have been identified in individuals presenting neurological manifestations co-occurring with hypotonia and early muscle anomalies, suggesting that AGO dysfunction directly affects the muscular system. The high sequence identity between AGO proteins, their partial functional redundancy, and the substantial overlap in clinical phenotypes support the hypothesis that shared molecular mechanisms underlie AGO-related disorders.

The project aims to disentangle muscle-intrinsic versus systemic effects of AGO dysfunction, assess redundancy between AGO1 and AGO2, and identify dysregulated gene regulatory networks resulting from impaired miRNA-mediated control.

Four objectives will be pursued:

1) Refine the clinical and phenotypic spectrum associated with pathogenic AGO variants in collaboration with clinical partners;

2) Generate and characterize muscle-specific AGO1 and AGO2 conditional knockout mouse models, including single and double knockouts;

3) Characterize membrane excitability, Ca²⁺ signaling, and EC coupling using electrophysiology and Ca²⁺ imaging in isolated muscle fibers from the mouse models;

4) Complement these functional analyses with molecular approaches and detailed structural characterization of muscle fiber subcompartments using confocal and super-resolution microscopy;

These analyses will integrate whole-organism phenotyping, tissue-level characterization, and cellular and transcriptomic investigations. Overall, the project will clarify how AGO dysfunction impairs muscle development and leads to hypotonia, potentially identifying shared therapeutic targets

The overarching scientific program that ties our teams revolves around the study of the physiopathology of the neuron and the skeletal muscle. We aim at deciphering basic biological mechanisms at the molecular, cell, tissue and organism levels to better understand their alterations in human pathologies to uncover new therapeutic approaches. To reach that goal, our teams combine multiscale, multidisciplinary approaches, taking advantage of the most appropriate models to conduct an ambitious research around three main research axes: (1) Physiology and cell biology of the neuromuscular system, (2) Cellular and molecular neurobiology and (3) Nuclear dynamics.

Required degree: Master’s degree or equivalent in Neuroscience, Physiology, Genetics or Biomedical Sciences

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