title: Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.
abstract: Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710. Electronic address: sandeep.singh@duke.edu.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Stogsdill
authors.affiliation: Department of Pediatrics, University of Maryland, School of Medicine, Baltimore, MD 21201.
authors.forename: Nisha S
authors.initials: NS
authors.lastname: Pulimood
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Hayley
authors.initials: H
authors.lastname: Dingsdale
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Louis-Jan
authors.initials: LJ
authors.lastname: Pilaz
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Il Hwan
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, University of Maryland, School of Medicine, Baltimore, MD 21201.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Manhaes
authors.affiliation: Department of Pediatrics, University of Maryland, School of Medicine, Baltimore, MD 21201.
authors.forename: Wandilson S
authors.initials: WS
authors.lastname: Rodrigues
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Arin
authors.initials: A
authors.lastname: Pamukcu
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Eray
authors.initials: E
authors.lastname: Enustun
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Ertuz
authors.affiliation: Biozentrum University of Basel, 4056 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710; Duke Institute for Brain Sciences (DIBS), Durham, NC 27710.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Soderling
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710; Duke Institute for Brain Sciences (DIBS), Durham, NC 27710.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Silver
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.affiliation: Department of Pediatrics, University of Maryland, School of Medicine, Baltimore, MD 21201.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Medina
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710; Duke Institute for Brain Sciences (DIBS), Durham, NC 27710. Electronic address: cagla.eroglu@dm.duke.edu.
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002522:Chlorocebus aethiops; D023882:Dominance, Ocular; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D020033:Protein Isoforms; C503127:Sparcl1 protein, mouse; C093438:neuroligin 1