title: IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway.
abstract: Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with X-linked mental retardation and autism spectrum disorder. We found that IL1RAPL1 regulates synapse formation of cortical neurons. To investigate how IL1RAPL1 controls synapse formation, we here screened IL1RAPL1-interacting proteins by affinity chromatography and mass spectroscopy. IL1RAPL1 interacted with Mcf2-like (Mcf2l), a Rho guanine nucleotide exchange factor, through the cytoplasmic Toll/IL-1 receptor domain. Knockdown of endogenous Mcf2l and treatment with an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of RhoA, suppressed IL1RAPL1-induced excitatory synapse formation of cortical neurons. Furthermore, we found that the expression of IL1RAPL1 affected the turnover of AMPA receptor subunits. Insertion of GluA1-containing AMPA receptors to the cell surface was decreased, whereas that of AMPA receptors composed of GluA2/3 was enhanced. Mcf2l knockdown and ROCK inhibitor treatment diminished the IL1RAPL1-induced changes of AMPA receptor subunit insertions. Our results suggest that Mcf2l-RhoA-ROCK signaling pathway mediates IL1RAPL1-dependent formation and stabilization of glutamatergic synapses of cortical neurons.
authors.affiliation: Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Moonjin
authors.initials: M
authors.lastname: Ra
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism*; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D053577:Interleukin-1 Receptor Accessory Protein; D018091:Receptors, AMPA; C568303:interleukin-1 receptor accessory protein-like 1, mouse; D018698:Glutamic Acid; D020742:rhoA GTP-Binding Protein