title: Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules.
abstract: Formation of chemical synapses requires exchange of organizing signals between the synaptic partners. Using synaptic vesicle aggregation in cultured neurons as a marker of presynaptic differentiation, we purified candidate presynaptic organizers from mouse brain. A major bioactive species was the extracellular domain of signal regulatory protein alpha (SIRP-alpha), a transmembrane immunoglobulin superfamily member concentrated at synapses. The extracellular domain of SIRP-alpha is cleaved and shed in a developmentally regulated manner. The presynaptic organizing activity of SIRP-alpha is mediated in part by CD47. SIRP-alpha homologues, SIRP-beta and -gamma also have synaptic vesicle clustering activity. The effects of SIRP-alpha are distinct from those of another presynaptic organizer, FGF22: the two proteins induced vesicle clusters of different sizes, differed in their ability to promote neurite branching, and acted through different receptors and signaling pathways. SIRP family proteins may act together with other organizing molecules to pattern synapses.
authors.affiliation: Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA. umemoh@umich.edu
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D051928:CD47 Antigen / Q000737:chemistry; D019556:COS Cells; D002454:Cell Differentiation; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D013569:Synapses / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051928:CD47 Antigen; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic