title: IL-1 receptor accessory protein-like 1 associated with mental retardation and autism mediates synapse formation by trans-synaptic interaction with protein tyrosine phosphatase δ.
abstract: Mental retardation (MR) and autism are highly heterogeneous neurodevelopmental disorders. IL-1-receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic MR and is associated with autism. Thus, the elucidation of the functional role of IL1RAPL1 will contribute to our understanding of the pathogenesis of these mental disorders. Here, we showed that knockdown of endogenous IL1RAPL1 in cultured cortical neurons suppressed the accumulation of punctate staining signals for active zone protein Bassoon and decreased the number of dendritic protrusions. Consistently, the expression of IL1RAPL1 in cultured neurons stimulated the accumulation of Bassoon and spinogenesis. The extracellular domain (ECD) of IL1RAPL1 was required and sufficient for the presynaptic differentiation-inducing activity, while both the ECD and cytoplasmic domain were essential for the spinogenic activity. Notably, the synaptogenic activity of IL1RAPL1 was specific for excitatory synapses. Furthermore, we identified presynaptic protein tyrosine phosphatase (PTP) δ as a major IL1RAPL1-ECD interacting protein by affinity chromatography. IL1RAPL1 interacted selectively with certain forms of PTPδ splice variants carrying mini-exon peptides in Ig-like domains. The synaptogenic activity of IL1RAPL1 was abolished in primary neurons from PTPδ knock-out mice. IL1RAPL1 showed robust synaptogenic activity in vivo when transfected into the cortical neurons of wild-type mice but not in PTPδ knock-out mice. These results suggest that IL1RAPL1 mediates synapse formation through trans-synaptic interaction with PTPδ. Our findings raise an intriguing possibility that the impairment of synapse formation may underlie certain forms of MR and autism as a common pathogenic pathway shared by these mental disorders.
authors.affiliation: Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Misato
authors.initials: M
authors.lastname: Yasumura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uemura
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Moonjin
authors.initials: M
authors.lastname: Ra
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D002846:Chromatography, Affinity / Q000379:methods; D055785:Gene Knockdown Techniques / Q000379:methods; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D008607:Intellectual Disability / Q000378:metabolism / Q000503:physiopathology*; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D014162:Transfection / Q000379:methods
chemical_list: C498441:Bsn protein, mouse; D053577:Interleukin-1 Receptor Accessory Protein; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C568303:interleukin-1 receptor accessory protein-like 1, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2