IL-1 Receptor Accessory Protein-Like 1 Associated with Mental Retardation and Autism Mediates Synapse Formation byTrans-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) ␦ as a major IL1RAPL1-ECD interacting protein by affinity chromatography. IL1RAPL1 interacted selectively with certain forms of PTP␦ splice variants carrying mini-exon peptides in Ig-like domains. The synaptogenic activity of IL1RAPL1 was abolished in primary neurons from PTP␦ knock-out mice. IL1RAPL1 showed robust synaptogenic activity in vivo when transfected into the cortical neurons of wild-type mice but not in PTP␦ knock-out mice. These results suggest that IL1RAPL1 mediates synapse formation through trans-synaptic interaction with PTP␦. 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.

Interleukin-1 Receptor Accessory Protein Organizes Neuronal Synaptogenesis as a Cell Adhesion Molecule

“…The entire coding sequences of mouse IL-1RAcP, IL-1RAcPb, SynCAM1, SynCAM2, SynCAM3, SALM1, SALM2, SALM3, SALM4 and IL-18RAcP were obtained by reverse transcription (RT)-PCR using mRNA prepared from mouse brains as a template and cloned into pcDNA3 vector (Invitrogen) or pcDNA3.1D/V5-His-TOPO vector (Invitrogen) to yield pIL-1RAcP, pIL-1RAcPb, pSynCAM1, pSynCAM2, pSynCAM3, pSALM1, pSALM2, pSALM3, pSALM4 and pCR-IL-18RAcP, respectively. The expression vectors for neurexin (NRXN) variants and neuroligin (NLGN) 1 were previously described (Uemura et al, 2010;Yoshida et al, 2011). The expression vectors for full-length proteins and ECDs of PTP␦, LAR (leukocyte common antigen-related), and PTP variants were previously described .…”

“…Ϫ B Ϫ -ECD-MH, LAR-ECD-MH, and PTP-ECD-MH were prepared as described previously (Uemura and Mishina, 2008;Yoshida et al, 2011) Cell aggregation assay. HEK293T cells cotransfected with expression vectors pEGFP-C1 and pIL-1RAcPb and those with ptagRFP-C1 (Evrogen) and pPTP␦, pLARA6, or pPTPA Ϫ were mixed at a density of 2.0 ϫ 10 6 cells/ml in HBSS containing 2 mM CaCl 2 and 1 mM MgCl 2 .…”

“…Splice variants with or without mini-exon (me) peptides in Iglike domains were reported for human and mouse PTP␦ (Pulido et al, 1995;Yoshida et al, 2011). Among 8 possible splice variants shown in Figure 7A, at least 6 variants (PTP␦, PTP␦A6, PTP␦A3, PTP␦A3B Ϫ , PTP␦A Ϫ and PTP␦A Ϫ B Ϫ ) were expressed in the developing mouse brain at P11 .…”

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

“…2B). Recent studies have established that alternative splicing events at the Ig domains of LAR-RPTPs determine their binding affinity toward postsynaptic ligands (3,5,6). Thus, we examined whether the GPC-4/PTPσ interaction is regulated by similar alternative splicing inserts (Fig.…”

Molecular Mechanism of Synapse Formation by Synaptic Organizer

“…GluRδ2-Cbln1-NRXN IL1RAPL1-PTPδ 17) TrkC-PTPσ 18) Slitrk3-PTPδ 19) PTP NRXN NRXN S4 17) GluRδ2 Cbln1 NRXN 4…”