Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development
Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is req...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-10, Vol.109 (44), p.18120-18125 |
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| creator | Anderson, Garret R Galfin, Timothy Xu, Wei Aoto, Jason Malenka, Robert C Südhof, Thomas C |
| description | Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis. |
| doi_str_mv | 10.1073/pnas.1216398109 |
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In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1216398109</identifier><identifier>PMID: 23074245</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Autism ; Autistic disorder ; Autistic Disorder - genetics ; Axons ; Biological Sciences ; cell adhesion ; Cell adhesion & migration ; Complementary DNA ; Dendritic Cells - metabolism ; Developmental biology ; Gene Knockdown Techniques ; genes ; Humans ; Membrane Proteins - genetics ; Molecules ; Mutation ; Nerve Net ; Nerve Tissue Proteins - genetics ; Neurochemistry ; neurodevelopment ; Neurons ; Pathogenesis ; Pervasive child development disorders ; Phenotypes ; RNA Interference ; RNA-protein interactions ; surveys ; synapse ; Synapses ; Synaptic transmission</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-10, Vol.109 (44), p.18120-18125</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Oct 30, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-f4d1bea01bff27fb0747ff52bb97f0ed4f75a582dee4d98d1a4c307849ba01123</citedby><cites>FETCH-LOGICAL-c591t-f4d1bea01bff27fb0747ff52bb97f0ed4f75a582dee4d98d1a4c307849ba01123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/44.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41829817$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41829817$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23074245$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anderson, Garret R</creatorcontrib><creatorcontrib>Galfin, Timothy</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Aoto, Jason</creatorcontrib><creatorcontrib>Malenka, Robert C</creatorcontrib><creatorcontrib>Südhof, Thomas C</creatorcontrib><title>Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. 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Galfin, Timothy ; Xu, Wei ; Aoto, Jason ; Malenka, Robert C ; Südhof, Thomas C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c591t-f4d1bea01bff27fb0747ff52bb97f0ed4f75a582dee4d98d1a4c307849ba01123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Autism</topic><topic>Autistic disorder</topic><topic>Autistic Disorder - genetics</topic><topic>Axons</topic><topic>Biological Sciences</topic><topic>cell adhesion</topic><topic>Cell adhesion & migration</topic><topic>Complementary DNA</topic><topic>Dendritic Cells - metabolism</topic><topic>Developmental biology</topic><topic>Gene Knockdown Techniques</topic><topic>genes</topic><topic>Humans</topic><topic>Membrane Proteins - genetics</topic><topic>Molecules</topic><topic>Mutation</topic><topic>Nerve Net</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Neurochemistry</topic><topic>neurodevelopment</topic><topic>Neurons</topic><topic>Pathogenesis</topic><topic>Pervasive child development disorders</topic><topic>Phenotypes</topic><topic>RNA Interference</topic><topic>RNA-protein interactions</topic><topic>surveys</topic><topic>synapse</topic><topic>Synapses</topic><topic>Synaptic transmission</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anderson, Garret R</creatorcontrib><creatorcontrib>Galfin, Timothy</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Aoto, Jason</creatorcontrib><creatorcontrib>Malenka, Robert C</creatorcontrib><creatorcontrib>Südhof, Thomas C</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anderson, Garret R</au><au>Galfin, Timothy</au><au>Xu, Wei</au><au>Aoto, Jason</au><au>Malenka, Robert C</au><au>Südhof, Thomas C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2012-10-30</date><risdate>2012</risdate><volume>109</volume><issue>44</issue><spage>18120</spage><epage>18125</epage><pages>18120-18125</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. 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| subjects | Autism Autistic disorder Autistic Disorder - genetics Axons Biological Sciences cell adhesion Cell adhesion & migration Complementary DNA Dendritic Cells - metabolism Developmental biology Gene Knockdown Techniques genes Humans Membrane Proteins - genetics Molecules Mutation Nerve Net Nerve Tissue Proteins - genetics Neurochemistry neurodevelopment Neurons Pathogenesis Pervasive child development disorders Phenotypes RNA Interference RNA-protein interactions surveys synapse Synapses Synaptic transmission |
| title | Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development |
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