title: Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb.
abstract: The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis.
authors.affiliation: Avenir/INSERM and Fondation pour la Recherche Médicale Team "Development and Plasticity of Neural Networks," Université Pierre et Marie Curie (UPMC) Paris 06, Unité Mixte de Recherche (UMR) 7102, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Scotto-Lomassese
authors.forename: Antoine
authors.initials: A
authors.lastname: Nissant
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mota
authors.forename: Marie
authors.initials: M
authors.lastname: Néant-Féry
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Charles A
authors.initials: CA
authors.lastname: Greer
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Lledo
authors.forename: Alain
authors.initials: A
authors.lastname: Trembleau
authors.forename: Isabelle
authors.initials: I
authors.lastname: Caillé
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009830:Olfactory Bulb / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D034741:RNA, Small Interfering / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D034741:RNA, Small Interfering; C497684:Fmr1 protein, mouse