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1.
Nature ; 462(7276): 1065-9, 2009 Dec 24.
Article in English | MEDLINE | ID: mdl-20010807

ABSTRACT

The majority of excitatory synapses in the mammalian CNS (central nervous system) are formed on dendritic spines, and spine morphology and distribution are critical for synaptic transmission, synaptic integration and plasticity. 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.


Subject(s)
Central Nervous System/growth & development , Central Nervous System/metabolism , Pyramidal Cells/cytology , Pyramidal Cells/growth & development , Semaphorins/metabolism , Synapses/physiology , Animals , Central Nervous System/cytology , Central Nervous System/drug effects , Central Nervous System/ultrastructure , Female , Gene Expression Regulation, Developmental , Male , Mice , Mice, Knockout , Neuropilin-1/metabolism , Neuropilin-2/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/ultrastructure , Recombinant Proteins/pharmacology , Semaphorins/genetics , Semaphorins/pharmacology , Signal Transduction , Synapses/drug effects , Synapses/ultrastructure
2.
Neuron ; 48(6): 949-64, 2005 Dec 22.
Article in English | MEDLINE | ID: mdl-16364899

ABSTRACT

Neuropilins, secreted semaphorin coreceptors, are expressed in discrete populations of spinal motor neurons, suggesting they provide critical guidance information for the establishment of functional motor circuitry. We show here that motor axon growth and guidance are impaired in the absence of Sema3A-Npn-1 signaling. Motor axons enter the limb precociously, showing that Sema3A controls the timing of motor axon in-growth to the limb. Lateral motor column (LMC) motor axons within spinal nerves are defasciculated as they grow toward the limb and converge in the plexus region. Medial and lateral LMC motor axons show dorso-ventral guidance defects in the forelimb. In contrast, Sema3F-Npn-2 signaling guides the axons of a medial subset of LMC neurons to the ventral limb, but plays no major role in regulating their fasciculation. Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of motor axon growth and guidance during the formation of spinal motor connections.


Subject(s)
Growth Cones/metabolism , Motor Neurons/metabolism , Neuropilins/metabolism , Semaphorins/metabolism , Signal Transduction/physiology , Spinal Cord/embryology , Animals , Body Patterning/physiology , Brachial Plexus/embryology , Cell Differentiation/physiology , Chick Embryo , Forelimb/embryology , Forelimb/innervation , Gene Expression Regulation, Developmental/physiology , Growth Cones/ultrastructure , Hindlimb/embryology , Hindlimb/innervation , Limb Buds/embryology , Limb Buds/innervation , Lumbosacral Plexus/embryology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Motor Neurons/cytology , Muscle, Skeletal/embryology , Muscle, Skeletal/innervation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Neuropilin-2/genetics , Neuropilin-2/metabolism , Semaphorin-3A/genetics , Semaphorin-3A/metabolism , Spinal Cord/cytology , Spinal Cord/metabolism
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