FMRP; MAP1B; cytoskeleton; fragile X messenger ribonucleoprotein; fragile X syndrome; microtubule-associated protein 1B; mouse; neuronal migration; neuroscience; Fmr1 protein, mouse; Animals; Mice; Fragile X Syndrome/metabolism; Fragile X Syndrome/genetics; Gene Knockdown Techniques; Fragile X Mental Retardation Protein/metabolism; Fragile X Mental Retardation Protein/genetics; Neurons/metabolism; Neurons/physiology; Microtubule-Associated Proteins/metabolism; Microtubule-Associated Proteins/genetics; Cell Movement; Mice, Knockout; Fragile X Mental Retardation Protein; Microtubule-Associated Proteins; Neurons; Neuroscience (all); Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all)
Abstract :
[en] The fragile X syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of autism spectrum disorder. FXS results from the absence of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal rostral migratory stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary Fmrp mRNA target implicated in these migratory defects is microtubule-associated protein 1B (MAP1B). Knocking down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.
Disciplines :
Neurology
Author, co-author :
Messaoudi, Salima; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Allam, Ada ; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Stoufflet, Julie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Paillard, Theo; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Le Ven, Anaïs; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France ; Institut Curie, Paris, France
Fouquet, Coralie; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Doulazmi, Mohamed; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Trembleau, Alain ; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France
Caille, Isabelle ; Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), Paris, France ; Université de Paris, Paris, France
Language :
English
Title :
FMRP regulates postnatal neuronal migration via MAP1B.
Fondation Jérôme Lejeune [FR] ANR - Agence Nationale de la Recherche [FR] NIDCD - National Institute on Deafness and Other Communication Disorders [US-MD]