title: Sema4D localizes to synapses and regulates GABAergic synapse development as a membrane-bound molecule in the mammalian hippocampus.
abstract: While numerous recent advances have contributed to our understanding of excitatory synapse formation, the processes that mediate inhibitory synapse formation remain poorly defined. Previously, we discovered that RNAi-mediated knockdown of a Class 4 Semaphorin, Sema4D, led to a decrease in the density of inhibitory synapses without an apparent effect on excitatory synapse formation. Our current work has led us to new insights about the molecular mechanisms by which Sema4D regulates GABAergic synapse development. Specifically, we report that the extracellular domain of Sema4D is proteolytically cleaved from the surface of neurons. However, despite this cleavage event, Sema4D signals through its extracellular domain as a membrane-bound, synaptically localized protein required in the postsynaptic membrane for proper GABAergic synapse formation. Thus, as Sema4D is one of only a few molecules identified thus far that preferentially regulates GABAergic synapse formation, these findings have important implications for our mechanistic understanding of this process.
authors.affiliation: National Center for Behavioral Genomics and Volen Center for Complex Systems, Department of Biology, Brandeis University, Waltham, MA 02454, USA.
authors.forename: Aram J
authors.initials: AJ
authors.lastname: Raissi
authors.forename: Emily K
authors.initials: EK
authors.lastname: Staudenmaier
authors.forename: Serena
authors.initials: S
authors.lastname: David
authors.forename: Linda
authors.initials: L
authors.lastname: Hu
authors.forename: Suzanne
authors.initials: S
authors.lastname: Paradis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D020318:Rats, Long-Evans; D039961:Semaphorins / Q000737:chemistry / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D039961:Semaphorins
keywords: GABAergic; Inhibitory synapse; Proteolytic cleavage; Sema4D
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