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.
Highlights
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with mental retardation (MR) and autism spectrum disorder (ASD) [1,2]
IL1RAPL1 stimulates the increase of dendritic protrusions through the Toll/IL-1 receptor (TIR) domain [14]
Total mouse forebrain proteins were extracted in 2M NaCl and the extract was loaded onto affinity columns of amylose resins coupled to IL1RAPL1ICD fused with maltose-binding protein (MBP) or to MBP as a control
Summary
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with mental retardation (MR) and autism spectrum disorder (ASD) [1,2]. The underlying causes of these mental disorders are extremely heterogeneous, molecular alterations in monogenic disorders may identify common pathogenic pathways shared by MR or ASD or both [12]. We found that presynaptic IL1RAPL1 controls in vivo synapse formation of olfactory sensory neurons of zebrafish [13]. Postsynaptic IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with presynaptic protein tyrosine phosphatase (PTP) d [14]. We proposed that the impairment of synapse formation underlies certain forms of MR and ASD as a common pathogenic pathway shared by these mental disorders [14].
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