Secreted Semaphorins Control Spine Distribution and Morphogenesis in the Postnatal CNS

Although it is known that different dendritic domains on the same neuron can receive distinct input, the molecular codes underlying these differences have been unknown. Here it is shown that a specific semaphorin signalling pathway, the Sema3F–Npn-2/PlexA4 cascade, that was previously associated with axonal guidance, is involved in the control of dendritic spine development and synapse formation in different dendritic arbours. Dendritic spines carry the majority of excitatory synapses, and spine morphology and distribution are critical for synaptic transmission, synaptic integration and plasticity. Here, signalling by the secreted semaphorin Sema3F is shown to control spine distribution along select dendritic processes, and distinct secreted semaphorin signalling events orchestrate CNS connectivity through the differential control of a variety of processes. The majority of excitatory synapses in the mammalian CNS (central nervous system) are formed on dendritic spines1, and spine morphology and distribution are critical for synaptic transmission2,3,4,5,6, synaptic integration and plasticity7. Here, we show that a secreted semaphorin, Sema3F, is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components neuropilin-2 (Npn-2, also known as Nrp2) and plexin A3 (PlexA3, also known as Plxna3), exhibit increased dentate gyrus (DG) granule cell (GC) and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn-2-/- brain slices cortical layer V and DG GCs exhibit increased mEPSC (miniature excitatory postsynaptic current) frequency. In contrast, a distinct Sema3A–Npn-1/PlexA4 signalling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn-2 to apical dendrites and of Npn-1 (also known as Nrp1) to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signalling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signalling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and the elaboration of dendritic morphology.