Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS

Abstract

The majority of excitatory synapses in the mammalian CNS are formed on dendritic spines1, and spine morphology and distribution are critical for synaptic transmission2–6, 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) and plexinA3 (PlexA3), 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 frequency. In contrast, a distinct Sema3A–Npn-1/PlexA4 signaling 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 to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signaling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signaling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and the elaboration of dendritic morphology.

Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling

“…Indeed, NRP1 was observed on basal and apical dendritic processes at 18DIV of primary mouse cortical neurons from E14.5 mouse embryos. 27 Aberrant dendritic or spine morphology and spine density in P21 and adult DG GCs of NRPs and PlexAs mutant mice further support the role of these dendritic semaphorin receptors in dendritic branching and spine morphogenesis. Sema3A may be secreted from non-neuronal cells such as astrocytes and smooth muscle cells as well as pre-and/or postsynaptic neurons.…”

“…However, Tran et al reported that the Sema3A signaling did not influence spine morphogenesis or distribution. 27 The Golgi-labeled Nrp1 Sema¡ and Sema3A ¡ / ¡ mouse brains did not exhibit spine density defects along apical dendrites of cortical layer V neurons. In addition, analysis of adult PlexA3 ¡ / ¡ and PlexA4 ¡ / ¡ mutant brains revealed that apical dendrite spine morphology was not altered in PlexA4 ¡ / ¡ .…”

“…94 To elucidate the significance of CRMP2 phosphorylation in the pathogenesis of Alzheimer disease, CRMP2 phosphorylation-deficient knock-in (crmp2 ki / ki ) mice were generated in which the serine residue at 522 of the protein was replaced with alanine. Intracerebroventricular injection of Ab [25][26][27][28][29][30][31][32][33][34][35] peptide, a neurotoxic fragment of Ab protein, in wild-type mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that the injection of the Ab [25][26][27][28][29][30][31][32][33][34][35] peptide caused impairment of both cognitive function and long-term potentiation in wild-type animals, but not in crmp2 ki / ki mice.…”

“…22 The type 3 semaphorins have been reported to play diverse functions in dendritic branching and synaptogenesis. [23][24][25][26][27] The first description of the role of Sema3A in dendrite morphogenesis was provided by slice overlay experiments. Sema3A was found to be a major component of this diffusible signal, and cortical neurons appeared to transduce this signal through NRP1 to direct the extension of apical and basal dendrites.…”

“…However, the type3 semaphorins could be a negative regulator of spine development, synaptic structure and synaptic transmission. [27][28][29] Kolodkin and his colleagues demonstrated that the Sema3F ¡ / ¡ , Nrp2 ¡ / ¡ and PlexA3 ¡ / ¡ mice, exhibited increased dentate gyrus (DG) granule cell (GC) and cortical layer V pyramidal neuron spine number and size as well as aberrant spine distribution. 27 In dissociated neurons in vitro, Sema3F promotes loss of spines and excitatory synapses.…”