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 α (SIRP-α), a transmembrane immunoglobulin superfamily member concentrated at synapses. The extracellular domain of SIRP-α is cleaved and shed in a developmentally regulated manner. The presynaptic organizing activity of SIRP-α is mediated in part by CD47. SIRP-α homologues, SIRP-β and -γ also have synaptic vesicle clustering activity. The effects of SIRP-α 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
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