title: Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development.
abstract: Prosap/Shank scaffolding proteins regulate the formation, organization, and plasticity of excitatory synapses. Mutations in SHANK family genes are implicated in autism spectrum disorder and other neuropsychiatric conditions. However, the molecular mechanisms underlying Shank function are not fully understood, and no study to date has examined the consequences of complete loss of all Shank proteins in vivo Here we characterize the single Drosophila Prosap/Shank family homolog. Shank is enriched at the postsynaptic membrane of glutamatergic neuromuscular junctions and controls multiple parameters of synapse biology in a dose-dependent manner. Both loss and overexpression of Shank result in defects in synaptic bouton number and maturation. We find that Shank regulates a noncanonical Wnt signaling pathway in the postsynaptic cell by modulating the internalization of the Wnt receptor Fz2. This study identifies Shank as a key component of synaptic Wnt signaling, defining a novel mechanism for how Shank contributes to synapse maturation during neuronal development.
  
  
  
  Haploinsufficiency for SHANK3 is one of the most prevalent monogenic causes of autism spectrum disorder, making it imperative to understand how the Shank family regulates neurodevelopment and synapse function. We created the first animal model lacking all Shank proteins and used the Drosophila neuromuscular junction, a model glutamatergic synapse, to characterize the role of Shank at synapses. We identified a novel function of Shank in synapse maturation via regulation of Wnt signaling in the postsynaptic cell.
authors.affiliation: Departments of Biology and Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 kpharris@mit.edu.
authors.forename: Kathryn P
authors.identifier: 0000-0003-1769-2587
authors.initials: KP
authors.lastname: Harris
authors.affiliation: Departments of Biology and Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Akbergenova
authors.affiliation: Departments of Biology and Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Cho
authors.affiliation: Departments of Biology and Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Maximilien S
authors.identifier: 0000-0001-9821-9585
authors.initials: MS
authors.lastname: Baas-Thomas
authors.affiliation: Departments of Biology and Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: J Troy
authors.identifier: 0000-0001-5576-2887
authors.initials: JT
authors.lastname: Littleton
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000071437:Axon Guidance / Q000502:physiology*; D004330:Drosophila / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; C122162:SHANK2 protein, human
keywords: Shank; Wnt signaling; postsynaptic scaffold; synaptic development