Repulsion and Attraction of Axons by Semaphorin3D Are Mediated by Different Neuropilins In Vivo

Department of Zoology and Anatomy, University of Wisconsin, Madison, Wisconsin 53706, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2004; 24(39):8428-35. DOI: 10.1523/JNEUROSCI.2349-04.2004
Source: PubMed


Class 3 semaphorins are known to repel and/or sometimes attract axons; however, their role in guiding developing axons in the CNS in vivo is still essentially unknown. We investigated the role of Semaphorin3D (Sema3D) in the formation of the early axon pathways in the zebrafish CNS. Morpholino knock-down shows that Sema3D is essential for the correct formation of two early axon pathways. Sema3D appears to guide axons of the nucleus of the medial longitudinal fasciculus (nucMLF) by repulsion and modulation of fasciculation. In contrast, Sema3D appears to be attractive to telencephalic neurons that form the anterior commissure (AC). Knock-down of Neuropilin-1A (Npn-1A) phenocopied the effects of Sema3D knock-down on the nucMLF axons, and knock-down of either Npn-1A or Npn-2B phenocopied the defects of the AC. Furthermore, simultaneous partial knock-down experiments demonstrated genetic interactions among Sema3D, Npn-1A, and Npn-2B. Together, these data support the hypothesis that Sema3D may act as a repellent through receptors containing Npn-1A and as an attractant via receptors containing Npn-1A and Npn-2B.

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    • "reviously ( Gaudin et al . , 2012 ) . Examination of the aberrant dorsal ADt axons suggests that Dcc is likely involved in the asymmetric out - growth of the ADt neurons ( Gao et al . 2012 ) . Previous studies have implicated other guidance factors such as neuropilins and semaphorin in the guidance of the anterior commissural axon to the midline ( Wolman et al . , 2004 ) . These and other factors such as Neogenin , a guidance receptor related to Dcc ( Wilson and Key , 2007 ; De Vries and Cooper , 2008 ) , may partially compensate for the loss of the Dcc function to mediate the AC formation ."
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    ABSTRACT: In the embryonic vertebrate brain, early born neurons establish highly stereotyped embryonic axonal tracts along which the neuronal interconnections form. To understand the mechanism underlying neuron axonal pathfinding within the embryonic scaffold of axon tracts, we studied zebrafish anterior dorsal telencephalic (ADt) neuron development. While previous studies suggest the ADt neuronal axons extend along a commissural tract [anterior commissure (AC)] and a descending ipsilateral tract [supraoptic tract (SOT)], it is unclear whether individual ADt neuronal axons choose specific projection paths at the intersection between the AC and the SOT. We labeled individual ADt neurons using a forebrain-specific promoter to drive expression of fluorescent proteins. We found the ADt axonal projection patterns were heterogeneous and correlated with their soma positions. Our results suggest that cell intrinsic differences along the dorsal ventral axis of the telencephalon regulate the axonal projection choices. Next, we determined that the guidance receptors roundabout2 (Robo2) and deleted in colorectal cancer (Dcc) were differentially expressed in the ADt neurons. We showed that knocking down Robo2 function by injecting antisense morpholino oligonucleotides abolished the ipsilateral SOT originating from the ADt neurons. Knocking down Dcc function did not prevent formation of the AC and the SOT. In contrast, the AC was specifically reduced when Netrin1 function was knocked down. Further mechanistic studies suggested that Robo2 responded to the repellent Slit signals and suppressed the attractive Netrin signals. These findings demonstrate how Robo2-Slit and Dcc-Netrin coordinate the axonal projection choices of the developing neurons in the vertebrate forebrain.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2012; 32(36):12589-602. DOI:10.1523/JNEUROSCI.6518-11.2012 · 6.34 Impact Factor
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    • "What is known is that Sema3d can bind to Nrp1 ectopically expressed by COS cells in vitro (Feiner et al., 1997). There is also some evidence in vivo that Nrp1 is important for Sema3d signaling in zebrafish, as Nrp1 knockdowns phenocopy Sema3d knockdowns; losing axon repulsion of axons from the nucleus of the medial longitudinal fasciculus (Wolman et al., 2004). The same study suggested that Nrp2 may be a constituent of the Sema3d receptor, as knockdown of Sema3d or Nrp2 showed a similar phenotype. "
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    ABSTRACT: The Class 3 Semaphorins (Sema3s) are a sub-family of proteins whose known biological roles are varied and growing. The mechanism of action of the Sema3s requires binding to transmembrane receptors that comprise heteromeric complexes of Neuropilins, Plexins and cell adhesion molecules (CAMs). However, knowledge of the receptor components of the Sema3s remains incomplete, and there may be receptor components which are as yet undiscovered. The receptor complexes of the Sema3s share receptor components with each other, and it is the specific combination of these components within a heteromeric complex that is thought to give rise to selective binding and signalling for individual Sema3s. This crosstalk makes it experimentally difficult to define a single holoreceptor for each Sema3. Furthermore, the receptor composition for a given Sema3 may differ between cell types, and change as a function of developmental state or pathological situation. Nevertheless, there are at least some known differences in the constitutive structure of the receptors for the Sema3s. For example in neural cells, Sema3a and Sema3f signal through different Neuropilins (Nrp1 and Nrp2 respectively) and L1cam only appears important for Sema3a signaling, while Nrcam forms a complex with Nrp2. Further complexity arises from crosstalk of other families of ligands (e.g., VEGF) with Sema3 receptor components. Thus the Sema3s, which have been shown as antagonists for each other, can also act as antagonists for other families of molecules. This review compiles experimental evidence describing the receptor components for the Sema3s, detailing the current state of knowledge of which components are important for signaling of each Sema3 before going on to consider possible future directions for the field.
    Frontiers in Cellular Neuroscience 07/2012; 6:28. DOI:10.3389/fncel.2012.00028 · 4.29 Impact Factor
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    • "Some semaphorins have been shown to exhibit both attractive and repulsive activities in vitro and in vivo (Song et al., 1998; Castellani et al., 2000, 2002; Wolman et al., 2004). Recent studies show novel mechanisms underlying the switch of Sema3E function from axonal repulsion to attraction (Chauvet et al., 2007; Bellon et al., 2010). "
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    ABSTRACT: Neural circuit formation requires the coordination of many complex developmental processes. First, neurons project axons over long distances to find their final targets and then establish appropriate connectivity essential for the formation of neuronal circuitry. Growth cones, the leading edges of axons, navigate by interacting with a variety of attractive and repulsive axon guidance cues along their trajectories and at final target regions. In addition to guidance of axons, neuronal polarization, neuronal migration, and dendrite development must be precisely regulated during development to establish proper neural circuitry. Semaphorins consist of a large protein family, which includes secreted and cell surface proteins, and they play important roles in many steps of neural circuit formation. The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors also mediate signaling by semaphorins. Upon semaphorin binding to their receptors, downstream signaling molecules transduce this event within cells to mediate further events, including alteration of microtubule and actin cytoskeletal dynamics. Here, I review recent studies on semaphorin signaling in vertebrate neural circuit assembly, with the goal of highlighting how this diverse family of cues and receptors imparts exquisite specificity to neural complex connectivity.
    Frontiers in Molecular Neuroscience 06/2012; 5:71. DOI:10.3389/fnmol.2012.00071 · 4.08 Impact Factor
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