04 juin 2017

La protéine IL1RAPL1 de déficience intellectuelle liée au X régule la complexité de la dendrite

Aperçu: G.M.
Les mutations et les délétions de la protéine du récepteur de l'interleukine-1 comme le gène 1 (IL1RAPL1), localisée sur le chromosome X, sont associées à une déficience intellectuelle (ID) et à un "trouble du spectre de l'autisme" (TSA).  
Les données révèlent une nouvelle fonction spécifique pour IL1RAPL1 dans la régulation de la morphologie de la dendrite qui peut aider à clarifier la façon dont les changements dans les voies régulées par IL1RAPL1 peuvent conduire à des troubles cognitifs chez l'homme. 

J Neurosci. 2017 Jun 2. pii: 3775-16. doi: 10.1523/JNEUROSCI.3775-16.2017.

The X-linked intellectual disability protein IL1RAPL1 regulates dendrite complexity

Author information

1
CNR Neuroscience Institute, Milan, Italy c.sala@in.cnr.it.
2
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
3
Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris 75014, France.
4
Fondazione Umberto Veronesi, Milan, Italy.
5
CNR Neuroscience Institute, Milan, Italy.
6
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Genoa, Italy.
7
U.O. of Neurophysiopathology and Diagnostic Epileptology, Foundation Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Neurological Institute Carlo Besta, Milan, Italy.
8
Institute of Molecular and Cellular Pharmacology (IPMC), Laboratory of Excellence Ion Channel Science and Therapeutics (LabEx ICST), CNRS UMR7275 and University of Nice-Sophia Antipolis, Valbonne, France.

Abstract

Mutations and deletions of Interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene, localized on X chromosome, are associated to intellectual disability (ID) and autism spectrum disorder (ASD). IL1RAPL1 protein is localized at the postsynaptic compartment of excitatory synapses and plays a role in synapse formation and stabilization. Here we characterized the role of IL1RAPL1 in regulating dendrite morphology using primary neuronal cultures and Il1rapl1-KO mice. We identified, associated to hippocampal cognitive impairment, an increased number of dendrite branching points in CA1 and CA2 hippocampal neurons of Il1rapl1-KO mice. Similarly, iPSCs-derived neurons form a patient carrying a null mutation of IL1RAPL1 gene have higher number of dendrites. In hippocampal neurons, the overexpression of full length IL1RAPL1 and mutants lacking part of C-terminal domains leads to a simplification of neuronal arborisation. This effect is abolished when we overexpressed mutants lacking part of N-terminal domains indicating that the IL1RAPL1 extracellular domain is required for regulating dendrite development. We also demonstrate that PTPδ interaction is not required for this activity, while IL1RAPL1 mediates the activity of IL-1β on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help to clarify how any changes in IL1RAPL1-regulated pathways can lead to cognitive disorders in humans.SIGNIFICANCE STATEMENTAbnormalities in the architecture of dendrites have been observed in a variety of neurodevelopmental, neurodegenerative and neuropsychiatric disorders. Here we show that the X-linked intellectual disability protein IL1RAPL1 regulates dendrite morphology of mice hippocampal neurons and iPSCs-derived neurons form patient carrying a null mutation of IL1RAPL1 gene. We also found that the extracellular domain of IL1RAPL1 is required for this effect, independently of the interaction with PTPδ but IL1RAPL1 mediates the activity of IL-1β on dendrite morphology. Our data reveal a novel specific function for IL1RAPL1 in regulating dendrite morphology that can help to clarify how any changes in IL1RAPL1-regulated pathways can lead to cognitive disorders in humans.
PMID: 28576939
DOI: 10.1523/JNEUROSCI.3775-16.2017

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