In vitro screening of signaling molecules involved in neural circuit formation has identified a large number of synaptogenic proteins. However, factors that drive synapse elimination remain elusive. Here, we report that bone morphogenetic protein 4 (BMP4) released from axons has the ability to eliminate synapses. We found fast axonal transport of BMP4 in dense-core vesicles, its exocytosis, and subsequent cell surface clustering via type I BMP receptors near synapses. BMP4 overexpression or knockout in culture reduced or increased presynaptic structures, respectively. The destabilizing effect of surface BMP4 clusters was limited to nearby synapses. In vivo knockout of BMP4 and subsequent two-photon imaging of synapse dynamics confirmed its critical role in maintaining an appropriate density of presynaptic components along the axon. These results suggest an essential role for perisynaptic clustering of BMP4 during development in the construction of functional neuronal circuits.
Keywords: BMP receptor; BMP4; axon; dense-core vesicles; exocytosis; hippocampus; in vivo imaging; synapse.
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