The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Tomoyuki Yoshida - One of the best experts on this subject based on the ideXlab platform.
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IL1RAPL1 knockout mice show spine density decrease learning deficiency hyperactivity and reduced anxiety like behaviours
Scientific Reports, 2015Co-Authors: Tomoyuki Yoshida, Misato Yasumura, Maya Yamazaki, Rie Natsume, Kouta Kanno, Takeshi Uemura, Keizo TakaoAbstract:IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.
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mechanisms of splicing dependent trans synaptic adhesion by ptpδ IL1RAPL1 il 1racp for synaptic differentiation
Nature Communications, 2015Co-Authors: Atsushi Yamagata, Tomoyuki Yoshida, Takeshi Uemura, Yusuke Sato, Sakurako Gotoito, Asami Maeda, Tomoko Shiroshima, Shiho IwasawaokamotoAbstract:Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP. Synapse formation depends on trans-synaptic interactions between selective pairs of pre- and postsynaptic adhesion molecules. Here, the authors establish the basis for the splice isoform-dependent selectivity of receptor protein tyrosine phosphatase δ as it forms trans-synaptic contacts with IL1RAPL1 and IL-1RAcP.
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Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation.
Nature Communications, 2015Co-Authors: Atsushi Yamagata, Tomoyuki Yoshida, Takeshi Uemura, Yusuke Sato, Asami Maeda, Tomoko Shiroshima, Sakurako Goto-ito, Shiho Iwasawa-okamoto, Hisashi Mori, Masayoshi MishinaAbstract:Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP. Synapse formation depends on trans-synaptic interactions between selective pairs of pre- and postsynaptic adhesion molecules. Here, the authors establish the basis for the splice isoform-dependent selectivity of receptor protein tyrosine phosphatase δ as it forms trans-synaptic contacts with IL1RAPL1 and IL-1RAcP.
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Synapse Formation in the Brain
Cortical Development, 2013Co-Authors: Masayoshi Mishina, Tomoyuki Yoshida, Misato Yasumura, Takeshi UemuraAbstract:Precise synaptic connections between nerve cells in the brain provide the basis of perception, learning, memory, and cognition. Synapse formation is the key step in the development of neuronal networks and requires the coordinate assembly of large numbers of protein complexes. Trans-synaptic cell adhesion molecules are thought to mediate target recognition and induction of pre- and postsynaptic specializations. Despite the wealth of information on the molecular mechanisms of glutamatergic synaptogenesis proposed by in vitro studies using neuronal cell culture models, evidence for their relevance to synaptogenesis in vivo has been lacking. Thus, fundamental questions about how glutamatergic synapses are formed in the mammalian brain have remained unanswered. On the other hand, there is clear in vivo evidence that GluRδ2, a member of the δ-type glutamate receptor (GluR), plays an essential role in cerebellar Purkinje cell (PC) synapse formation. We found that a significant number of PC spines lack synaptic contacts with parallel fiber (PF) terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Recently, we have shown that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through Cbln1 mediates PF-PC synapse formation. The assembly stoichiometry of the synaptogenic GluRδ2-Cbln1-NRXN1β triad provides the molecular insight into the mechanism of PF-PC synapse formation in the cerebellum. IL1-receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic mental retardation and autism. We have found that postsynaptic IL1RAPL1 mediates excitatory synapse formation of cortical neurons through trans-synaptic interaction with specific variants of presynaptic protein tyrosine phosphatase-δ. These results imply the impaired synapse formation as a common pathogenic pathway shared by mental retardation and autism.
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IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through rhoa signaling pathway
PLOS ONE, 2013Co-Authors: Takashi Hayashi, Tomoyuki Yoshida, Masayoshi Mishina, Moonjin Ra, Ryo TaguchiAbstract: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.
Masayoshi Mishina - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation.
Nature Communications, 2015Co-Authors: Atsushi Yamagata, Tomoyuki Yoshida, Takeshi Uemura, Yusuke Sato, Asami Maeda, Tomoko Shiroshima, Sakurako Goto-ito, Shiho Iwasawa-okamoto, Hisashi Mori, Masayoshi MishinaAbstract:Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP. Synapse formation depends on trans-synaptic interactions between selective pairs of pre- and postsynaptic adhesion molecules. Here, the authors establish the basis for the splice isoform-dependent selectivity of receptor protein tyrosine phosphatase δ as it forms trans-synaptic contacts with IL1RAPL1 and IL-1RAcP.
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Synapse Formation in the Brain
Cortical Development, 2013Co-Authors: Masayoshi Mishina, Tomoyuki Yoshida, Misato Yasumura, Takeshi UemuraAbstract:Precise synaptic connections between nerve cells in the brain provide the basis of perception, learning, memory, and cognition. Synapse formation is the key step in the development of neuronal networks and requires the coordinate assembly of large numbers of protein complexes. Trans-synaptic cell adhesion molecules are thought to mediate target recognition and induction of pre- and postsynaptic specializations. Despite the wealth of information on the molecular mechanisms of glutamatergic synaptogenesis proposed by in vitro studies using neuronal cell culture models, evidence for their relevance to synaptogenesis in vivo has been lacking. Thus, fundamental questions about how glutamatergic synapses are formed in the mammalian brain have remained unanswered. On the other hand, there is clear in vivo evidence that GluRδ2, a member of the δ-type glutamate receptor (GluR), plays an essential role in cerebellar Purkinje cell (PC) synapse formation. We found that a significant number of PC spines lack synaptic contacts with parallel fiber (PF) terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Recently, we have shown that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through Cbln1 mediates PF-PC synapse formation. The assembly stoichiometry of the synaptogenic GluRδ2-Cbln1-NRXN1β triad provides the molecular insight into the mechanism of PF-PC synapse formation in the cerebellum. IL1-receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic mental retardation and autism. We have found that postsynaptic IL1RAPL1 mediates excitatory synapse formation of cortical neurons through trans-synaptic interaction with specific variants of presynaptic protein tyrosine phosphatase-δ. These results imply the impaired synapse formation as a common pathogenic pathway shared by mental retardation and autism.
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IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through rhoa signaling pathway
PLOS ONE, 2013Co-Authors: Takashi Hayashi, Tomoyuki Yoshida, Masayoshi Mishina, Moonjin Ra, Ryo TaguchiAbstract: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.
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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
The Journal of Neuroscience, 2011Co-Authors: Tomoyuki Yoshida, Moonjin Ra, Ryo Taguchi, Misato Yasumura, Takeshi Uemura, Yoichiro Iwakura, Masayoshi MishinaAbstract: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.
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zebrafish orthologue of mental retardation protein IL1RAPL1 regulates presynaptic differentiation
Molecular and Cellular Neuroscience, 2008Co-Authors: Tomoyuki Yoshida, Masayoshi MishinaAbstract:IL1-receptor accessory protein-like 1 (IL1RAPL1), a member of interleukin-1/toll receptor (TIR) family, is responsible for a nonsyndromic form of mental retardation (MR). The zebrafish orthologue of mammalian IL1RAPL1, designated as IL1RAPL1b, was expressed widely in the brain and in the olfactory placode. We employed an olfactory sensory neuron-specific gene manipulation system in combination with in vivo imaging of transparent zebrafish embryos to examine the functional role of IL1RAPL1b in synaptic vesicle accumulation and subsequent morphological remodeling of axon terminals, the characteristic features of presynaptic differentiation of zebrafish olfactory sensory neurons during synapse formation. Antisense morpholino oligonucleotide against IL1RAPL1b suppressed both the synaptic vesicle accumulation and axon terminal remodeling. Consistently, the overexpression of IL1RAPL1b stimulated synaptic vesicle accumulation. Swapping the carboxyl-terminal domain of IL1RAPL1b with that of mouse IL-1 receptor accessory protein abolished the stimulatory effect. On the other hand, a substitution mutation in the TIR domain suppressed the morphological remodeling of axon terminals. Thus, the regulation of synaptic vesicle accumulation and subsequent morphological remodeling by IL1RAPL1b appeared to be mediated by distinct domains. These results suggest that IL1RAPL1b plays an important role in presynaptic differentiation during synapse formation.
Nancy Choucair - One of the best experts on this subject based on the ideXlab platform.
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Evidence that homozygous PTPRD gene microdeletion causes trigonocephaly, hearing loss, and intellectual disability
Molecular Cytogenetics, 2015Co-Authors: Nancy Choucair, Cecile Mignon-ravix, Joelle Abou Ghoch, Ali Fawaz, Andre Megarbane, Laurent Villard, Pierre Cacciagli, Eliane ChoueryAbstract:Background: The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID). Results: We describe a 30 month old boy with severe intellectual disability, trigonocephaly and dysmorphic facial features such as a midface hypoplasia, a flat nose, a depressed nasal bridge, hypertelorism, a long philtrum and a drooping mouth. Microarray chromosomal analysis revealed the presence of a homozygous deletion involving the PTPRD gene, located on chromosome 9p22.3. Reverse Transcription PCR (RT- PCR) amplifications all along the gene failed to amplify the patient's cDNA in fibroblasts, indicating the presence of two null PTPRD alleles. Synaptic PTPRD interacts with IL1RAPL1 which defects have been associated with intellectual disability (ID) and autism spectrum disorder. The absence of the PTPRD transcript leads to a decrease in the expression of IL1RAPL1. These results suggest the direct involvement of PTPRD in ID, which is consistent with the PTPRD -/- mice phenotype. Deletions of PTPRD have been previously suggested as a cause of trigonocephaly in patients with monosomy 9p and genome-wide association study suggested variations in PTPRD are associated with hearing loss. Conclusions: The deletion identified in the reported patient supports previous hypotheses on its function in ID and hearing loss. However, its involvement in the occurrence of metopic synostosis is still to be discussed as more investigation of patients with the 9p monosomy syndrome is required.
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evidence that homozygous ptprd gene microdeletion causes trigonocephaly hearing loss and intellectual disability
Molecular Cytogenetics, 2015Co-Authors: Nancy Choucair, Ali Fawaz, Pierre Cacciagli, Cecile Mignonravix, Joelle Abou Ghoch, Andre MegarbaneAbstract:Background The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID).
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
American Journal of Medical Genetics Part A, 2014Co-Authors: Cecile Mignon-ravix, Nancy Choucair, Andre Megarbane, Pierre Cacciagli, Cornel Popovici, Chantal Missirian, Mathieu Milh, Tiffany Busa, Sophie Julia, Nadine GirardAbstract:High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed. © 2014 Wiley Periodicals, Inc.
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
American journal of medical genetics. Part A, 2014Co-Authors: Cecile Mignon-ravix, Nancy Choucair, Andre Megarbane, Pierre Cacciagli, Cornel Popovici, Chantal Missirian, Mathieu Milh, Tiffany Busa, Sophie Julia, Nadine GirardAbstract:High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.
Takeshi Uemura - One of the best experts on this subject based on the ideXlab platform.
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IL1RAPL1 knockout mice show spine density decrease learning deficiency hyperactivity and reduced anxiety like behaviours
Scientific Reports, 2015Co-Authors: Tomoyuki Yoshida, Misato Yasumura, Maya Yamazaki, Rie Natsume, Kouta Kanno, Takeshi Uemura, Keizo TakaoAbstract:IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.
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mechanisms of splicing dependent trans synaptic adhesion by ptpδ IL1RAPL1 il 1racp for synaptic differentiation
Nature Communications, 2015Co-Authors: Atsushi Yamagata, Tomoyuki Yoshida, Takeshi Uemura, Yusuke Sato, Sakurako Gotoito, Asami Maeda, Tomoko Shiroshima, Shiho IwasawaokamotoAbstract:Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP. Synapse formation depends on trans-synaptic interactions between selective pairs of pre- and postsynaptic adhesion molecules. Here, the authors establish the basis for the splice isoform-dependent selectivity of receptor protein tyrosine phosphatase δ as it forms trans-synaptic contacts with IL1RAPL1 and IL-1RAcP.
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Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation.
Nature Communications, 2015Co-Authors: Atsushi Yamagata, Tomoyuki Yoshida, Takeshi Uemura, Yusuke Sato, Asami Maeda, Tomoko Shiroshima, Sakurako Goto-ito, Shiho Iwasawa-okamoto, Hisashi Mori, Masayoshi MishinaAbstract:Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP. Synapse formation depends on trans-synaptic interactions between selective pairs of pre- and postsynaptic adhesion molecules. Here, the authors establish the basis for the splice isoform-dependent selectivity of receptor protein tyrosine phosphatase δ as it forms trans-synaptic contacts with IL1RAPL1 and IL-1RAcP.
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Synapse Formation in the Brain
Cortical Development, 2013Co-Authors: Masayoshi Mishina, Tomoyuki Yoshida, Misato Yasumura, Takeshi UemuraAbstract:Precise synaptic connections between nerve cells in the brain provide the basis of perception, learning, memory, and cognition. Synapse formation is the key step in the development of neuronal networks and requires the coordinate assembly of large numbers of protein complexes. Trans-synaptic cell adhesion molecules are thought to mediate target recognition and induction of pre- and postsynaptic specializations. Despite the wealth of information on the molecular mechanisms of glutamatergic synaptogenesis proposed by in vitro studies using neuronal cell culture models, evidence for their relevance to synaptogenesis in vivo has been lacking. Thus, fundamental questions about how glutamatergic synapses are formed in the mammalian brain have remained unanswered. On the other hand, there is clear in vivo evidence that GluRδ2, a member of the δ-type glutamate receptor (GluR), plays an essential role in cerebellar Purkinje cell (PC) synapse formation. We found that a significant number of PC spines lack synaptic contacts with parallel fiber (PF) terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Recently, we have shown that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through Cbln1 mediates PF-PC synapse formation. The assembly stoichiometry of the synaptogenic GluRδ2-Cbln1-NRXN1β triad provides the molecular insight into the mechanism of PF-PC synapse formation in the cerebellum. IL1-receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic mental retardation and autism. We have found that postsynaptic IL1RAPL1 mediates excitatory synapse formation of cortical neurons through trans-synaptic interaction with specific variants of presynaptic protein tyrosine phosphatase-δ. These results imply the impaired synapse formation as a common pathogenic pathway shared by mental retardation and autism.
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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
The Journal of Neuroscience, 2011Co-Authors: Tomoyuki Yoshida, Moonjin Ra, Ryo Taguchi, Misato Yasumura, Takeshi Uemura, Yoichiro Iwakura, Masayoshi MishinaAbstract: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.
Andre Megarbane - One of the best experts on this subject based on the ideXlab platform.
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Evidence that homozygous PTPRD gene microdeletion causes trigonocephaly, hearing loss, and intellectual disability
Molecular Cytogenetics, 2015Co-Authors: Nancy Choucair, Cecile Mignon-ravix, Joelle Abou Ghoch, Ali Fawaz, Andre Megarbane, Laurent Villard, Pierre Cacciagli, Eliane ChoueryAbstract:Background: The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID). Results: We describe a 30 month old boy with severe intellectual disability, trigonocephaly and dysmorphic facial features such as a midface hypoplasia, a flat nose, a depressed nasal bridge, hypertelorism, a long philtrum and a drooping mouth. Microarray chromosomal analysis revealed the presence of a homozygous deletion involving the PTPRD gene, located on chromosome 9p22.3. Reverse Transcription PCR (RT- PCR) amplifications all along the gene failed to amplify the patient's cDNA in fibroblasts, indicating the presence of two null PTPRD alleles. Synaptic PTPRD interacts with IL1RAPL1 which defects have been associated with intellectual disability (ID) and autism spectrum disorder. The absence of the PTPRD transcript leads to a decrease in the expression of IL1RAPL1. These results suggest the direct involvement of PTPRD in ID, which is consistent with the PTPRD -/- mice phenotype. Deletions of PTPRD have been previously suggested as a cause of trigonocephaly in patients with monosomy 9p and genome-wide association study suggested variations in PTPRD are associated with hearing loss. Conclusions: The deletion identified in the reported patient supports previous hypotheses on its function in ID and hearing loss. However, its involvement in the occurrence of metopic synostosis is still to be discussed as more investigation of patients with the 9p monosomy syndrome is required.
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evidence that homozygous ptprd gene microdeletion causes trigonocephaly hearing loss and intellectual disability
Molecular Cytogenetics, 2015Co-Authors: Nancy Choucair, Ali Fawaz, Pierre Cacciagli, Cecile Mignonravix, Joelle Abou Ghoch, Andre MegarbaneAbstract:Background The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID).
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
American Journal of Medical Genetics Part A, 2014Co-Authors: Cecile Mignon-ravix, Nancy Choucair, Andre Megarbane, Pierre Cacciagli, Cornel Popovici, Chantal Missirian, Mathieu Milh, Tiffany Busa, Sophie Julia, Nadine GirardAbstract:High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed. © 2014 Wiley Periodicals, Inc.
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
American journal of medical genetics. Part A, 2014Co-Authors: Cecile Mignon-ravix, Nancy Choucair, Andre Megarbane, Pierre Cacciagli, Cornel Popovici, Chantal Missirian, Mathieu Milh, Tiffany Busa, Sophie Julia, Nadine GirardAbstract:High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.
