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.
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We thank M. Delannoy and the Johns Hopkins University School of Medicine Microscope Facility for assistance with EM analysis; M. Pucak and the NINDS Multi-photon Core Facility at JHMI; D. Bergles and D. Linden for comments on the manuscript; R. Yuste for helpful discussions; K. Chak and members of the Kolodkin and Ginty laboratories for assistance throughout the course of this project. This work was supported by R01 MH59199 to D.D.G. and A.L.K.; NRSA F32 NS051003 to T.S.T.; R01 DC-006881 and NSF DB1-0420580 to M.E.R.; and P50 MH06883 to R.L.H. and D.D.G. D.D.G., R.L.H. and A.L.K. are investigators of the Howard Hughes Medical Institute.
Author Contributions T.S.T. performed most of the experiments and data analysis, and M.E.R. performed most of the non-serial TEM analysis. R.L.C. and R.L.H. performed and analysed whole-cell patch recordings. L.C. and M.T.-L. participated in the analysis of Plexin mutant mice. D.J. provided technical support. T.S.T., D.D.G. and A.L.K. designed the experiments and wrote the manuscript.
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Tran, T., Rubio, M., Clem, R. et al. Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462, 1065–1069 (2009). https://doi.org/10.1038/nature08628
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