Synaptic Specificity Is Generated by the Synaptic Guidepost Protein SYG-2 and Its Receptor, SYG-1

Howard Hughes Medical Institute, Department of Anatomy, The University of California, San Francisco, San Francisco, CA 94143, USA.
Cell (Impact Factor: 33.12). 04/2004; 116(6):869-81. DOI: 10.1016/S0092-8674(04)00251-X
Source: PubMed

ABSTRACT Synaptic connections in the nervous system are directed onto specific cellular and subcellular targets. Synaptic guidepost cells in the C. elegans vulval epithelium drive synapses from the HSNL motor neuron onto adjacent target neurons and muscles. Here, we show that the transmembrane immunoglobulin superfamily protein SYG-2 is a central component of the synaptic guidepost signal. SYG-2 is expressed transiently by primary vulval epithelial cells during synapse formation. SYG-2 binds SYG-1, the receptor on HSNL, and directs SYG-1 accumulation and synapse formation to adjacent regions of HSNL. syg-1 and syg-2 mutants have defects in synaptic specificity; the HSNL neuron forms fewer synapses onto its normal targets and forms ectopic synapses onto inappropriate targets. Misexpression of SYG-2 in secondary epithelial cells causes aberrant accumulation of SYG-1 and synaptic markers in HSNL adjacent to the SYG-2-expressing cells. Our results indicate that local interactions between immunoglobulin superfamily proteins can determine specificity during synapse formation.

Download full-text


Available from: Richard Fetter, Aug 25, 2015
  • Source
    • "IrreC/Rst and Kirre are orthologues of the C. elegans protein SYG-1, which regulates synaptogenesis of the hermaphrodite-specifi c motor neuron (HSNL) (Shen & Bargmann, 2003). The C. elegans homologue of SNS and Hbs, SYG-2, on adjacent vulva epithelial guidepost cells recruits SYG-1 in HSNL neurons to the locations in the HSNL axon where presynaptic terminals form that persist into adulthood (Shen et al., 2004). Kirre-like proteins have also been reported to occur in the vertebrate kidney (refl ected in the alternate term " Neph proteins " ), where they are required to form slit diaphragm junctions between the podocytes (Sellin et al., 2002; Ihalmo et al., 2003; Sun et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Each neuropil module, or cartridge, in the fly's lamina has a fixed complement of cells. Of five types of monopolar cell interneurons, only L4 has collaterals that invade neighboring cartridges. In the proximal lamina, these collaterals form reciprocal synapses with both the L2 of their own cartridge and the L4 collateral branches from two other neighboring cartridges. During synaptogenesis, L4 collaterals strongly express the cell adhesion protein Kirre, a member of the irre cell recognition module (IRM) group of proteins ( Fischbach et al., 2009 , J Neurogenet, 23, 48-67). The authors show by mutant analysis and gene knockdown techniques that L4 neurons develop their lamina collaterals in the absence of this cell adhesion protein. Using electron microscopy (EM), the authors demonstrate, however, that without Kirre protein these L4 collaterals selectively form fewer synapses. The collaterals of L4 neurons of various genotypes reconstructed from serial-section EM revealed that the number of postsynaptic sites was dramatically reduced in the absence of Kirre, almost eliminating any synaptic input to L4 neurons. A significant reduction of presynaptic sites was also detected in kirre(0) mutants and gene knockdown flies using RNA interference. L4 neuron reciprocal synapses are thus almost eliminated. A presynaptic marker, Brp-short(GFP) confirmed these data using confocal microscopy. This study reveals that removing Kirre protein specifically disrupts the functional L4 synaptic network in the Drosophila lamina.
    Journal of neurogenetics 04/2014; 28(3-4). DOI:10.3109/01677063.2014.883390 · 1.38 Impact Factor
  • Source
    • "For this purpose, we used syg-1;syg-2 double-mutant animals and coinjected them with chimeric syg-1 and chimeric syg-2 under the unc-86 and egl-17 promoters, respectively. The egl- 17 promoter drives expression in the secondary vulva epithelial cells, and expression of syg-2 with this promoter has been shown to reconstitute synapses in an axonal fragment contacting these cells (Figures 6A–6D) (Shen et al., 2004). We observed that chimeras with Drosophila and mouse D1s can rescue the syg-1;syg-2 phenotype (Figures 6E and 6F). "
    [Show abstract] [Hide abstract]
    ABSTRACT: SYG-1 and SYG-2 are multipurpose cell adhesion molecules (CAMs) that have evolved across all major animal taxa to participate in diverse physiological functions, ranging from synapse formation to formation of the kidney filtration barrier. In the crystal structures of several SYG-1 and SYG-2 orthologs and their complexes, we find that SYG-1 orthologs homodimerize through a common, bispecific interface that similarly mediates an unusual orthogonal docking geometry in the heterophilic SYG-1/SYG-2 complex. C. elegans SYG-1's specification of proper synapse formation in vivo closely correlates with the heterophilic complex affinity, which appears to be tuned for optimal function. Furthermore, replacement of the interacting domains of SYG-1 and SYG-2 with those from CAM complexes that assume alternative docking geometries or the introduction of segmental flexibility compromised synaptic function. These results suggest that SYG extracellular complexes do not simply act as "molecular velcro" and that their distinct structural features are important in instructing synaptogenesis. PAPERFLICK:
    Cell 01/2014; 156(3):482-94. DOI:10.1016/j.cell.2014.01.004 · 33.12 Impact Factor
  • Source
    • "For example, such an instructive role is mediated in the retina by the sidekicks and Dscam Ig-domain proteins, which ensure proper lamina connectivity Yamagata et al., 2002 and 2008). Similarly, in C. elegans the Ig-domain proteins Syg-1 and Syg-2 are not directly related to synapse formation, but appear to guide synapse formation to the right place in one particular neuron (Shen et al., 2004). Similarly, adhesive interactions mediated by the Ig proteins neurofascin and CHL1 spatially define synapses formed by basket interneurons and stellate axons, respectively, onto Purkinje cells on a subcellular level (Ango et al., 2004 and 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that include neurexins and neuroligins, Ig-domain proteins such as SynCAMs, receptor phosphotyrosine kinases and phosphatases, and several leucine-rich repeat proteins have been identified. These synaptic cell adhesion molecules use characteristic extracellular domains to perform complementary roles in organizing synaptic junctions that are only now being revealed. The importance of synaptic cell adhesion molecules for brain function is highlighted by recent findings implicating several such molecules, notably neurexins and neuroligins, in schizophrenia and autism.
    Cold Spring Harbor perspectives in biology 01/2012; 4(4):a005694. DOI:10.1101/cshperspect.a005694 · 8.23 Impact Factor
Show more