Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Development 135 (23): 3839-3848

Dscam guides embryonic axons by Netrin-dependent and -independent functions

Gracie L. Andrews1, Shawna Tanglao1, W. Todd Farmer1, Steves Morin2, Steven Brotman1, Michael A. Berberoglu1, Hilary Price1, George C. Fernandez3, Grant S. Mastick1, Frédéric Charron2,4, and Thomas Kidd1,*

1 Department of Biology/ms 314, University of Nevada, Reno, NV 89557, USA.
2 Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
3 Center for Research Design and Analysis/ms 088, University of Nevada, Reno, NV 89557, USA.
4 Department of Medicine, University of Montreal, Montreal, Quebec, Canada.

* Author for correspondence (e-mail: tkidd{at}unr.edu)

Accepted for publication 22 September 2008.

Abstract: Developing axons are attracted to the CNS midline by Netrin proteins and other as yet unidentified signals. Netrin signals are transduced in part by Frazzled (Fra)/DCC receptors. Genetic analysis in Drosophila indicates that additional unidentified receptors are needed to mediate the attractive response to Netrin. Analysis of Bolwig's nerve reveals that Netrin mutants have a similar phenotype to Down Syndrome Cell Adhesion Molecule (Dscam) mutants. Netrin and Dscam mutants display dose sensitive interactions, suggesting that Dscam could act as a Netrin receptor. We show using cell overlay assays that Netrin binds to fly and vertebrate Dscam, and that Dscam binds Netrin with the same affinity as DCC. At the CNS midline, we find that Dscam and its paralog Dscam3 act redundantly to promote midline crossing. Simultaneous genetic knockout of the two Dscam genes and the Netrin receptor fra produces a midline crossing defect that is stronger than the removal of Netrin proteins, suggesting that Dscam proteins also function in a pathway parallel to Netrins. Additionally, overexpression of Dscam in axons that do not normally cross the midline is able to induce ectopic midline crossing, consistent with an attractive receptor function. Our results support the model that Dscam proteins function as attractive receptors for Netrin and also act in parallel to Frazzled/DCC. Furthermore, the results suggest that Dscam proteins have the ability to respond to multiple ligands and act as receptors for an unidentified midline attractive cue. These functions in axon guidance have implications for the pathogenesis of Down Syndrome.

Key Words: Drosophila genetics • Axon guidance • Body patterning • Cell migration • Central nervous system • Signal transduction

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
c-Jun N-terminal Kinase 1 (JNK1) Is Required for Coordination of Netrin Signaling in Axon Guidance.
C. Qu, W. Li, Q. Shao, T. Dwyer, H. Huang, T. Yang, and G. Liu (2013)
J. Biol. Chem. 288, 1883-1895
   Abstract »    Full Text »    PDF »
Drosophila Vap-33 Is Required for Axonal Localization of Dscam Isoforms.
Z. Yang, S. U. Huh, J. M. Drennan, H. Kathuria, J. S. Martinez, H. Tsuda, M. C. Hall, and J. C. Clemens (2012)
J. Neurosci. 32, 17241-17250
   Abstract »    Full Text »    PDF »
DSCAM Contributes to Dendrite Arborization and Spine Formation in the Developing Cerebral Cortex.
K. R. Maynard and E. Stein (2012)
J. Neurosci. 32, 16637-16650
   Abstract »    Full Text »    PDF »
Expanding the Ig Superfamily Code for Laminar Specificity in Retina: Expression and Role of Contactins.
M. Yamagata and J. R. Sanes (2012)
J. Neurosci. 32, 14402-14414
   Abstract »    Full Text »    PDF »
Down Syndrome Cell Adhesion Molecule (DSCAM) Associates with Uncoordinated-5C (UNC5C) in Netrin-1-mediated Growth Cone Collapse.
A. A. Purohit, W. Li, C. Qu, T. Dwyer, Q. Shao, K.-L. Guan, and G. Liu (2012)
J. Biol. Chem. 287, 27126-27138
   Abstract »    Full Text »    PDF »
Genetic Analysis of DSCAM's Role as a Netrin-1 Receptor in Vertebrates.
E. Palmesino, P. C. G. Haddick, M. Tessier-Lavigne, and A. Kania (2012)
J. Neurosci. 32, 411-416
   Abstract »    Full Text »    PDF »
Motoneurons are essential for vascular pathfinding.
A. H. Lim, A. Suli, K. Yaniv, B. Weinstein, D. Y. Li, and C.-B. Chien (2011)
Development 138, 3847-3857
   Abstract »    Full Text »    PDF »
Netrins: versatile extracellular cues with diverse functions.
K. L. W. Sun, J. P. Correia, and T. E. Kennedy (2011)
Development 138, 2153-2169
   Abstract »    Full Text »    PDF »
Mechanisms and Molecules of Neuronal Wiring: A Primer.
A. L. Kolodkin and M. Tessier-Lavigne (2011)
Cold Spring Harb Perspect Biol 3, a001727
   Abstract »    Full Text »    PDF »
Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes.
S. Sharma, X. Gao, D. Londono, S. E. Devroy, K. N. Mauldin, J. T. Frankel, J. M. Brandon, D. Zhang, Q.-Z. Li, M. B. Dobbs, et al. (2011)
Hum. Mol. Genet. 20, 1456-1466
   Abstract »    Full Text »    PDF »
The Growth Cone Cytoskeleton in Axon Outgrowth and Guidance.
E. W. Dent, S. L. Gupton, and F. B. Gertler (2011)
Cold Spring Harb Perspect Biol 3, a001800
   Abstract »    Full Text »    PDF »
Self-avoidance and Tiling: Mechanisms of Dendrite and Axon Spacing.
W. B. Grueber and A. Sagasti (2010)
Cold Spring Harb Perspect Biol 2, a001750
   Abstract »    Full Text »    PDF »
Navigating Intermediate Targets: The Nervous System Midline.
B. J. Dickson and Y. Zou (2010)
Cold Spring Harb Perspect Biol 2, a002055
   Abstract »    Full Text »    PDF »
Drosophila Neurexin IV Interacts with Roundabout and Is Required for Repulsive Midline Axon Guidance.
S. Banerjee, K. Blauth, K. Peters, S. L. Rogers, A. S. Fanning, and M. A. Bhat (2010)
J. Neurosci. 30, 5653-5667
   Abstract »    Full Text »    PDF »
Axons find their way in the snow.
Y. Zou (2009)
Development 136, 2135-2139
   Abstract »    Full Text »    PDF »
Crossing the Line.
T. Kidd (2009)
Science 324, 893-894
   Abstract »    Full Text »    PDF »
Molecules and mechanisms of dendrite development in Drosophila.
M. M. Corty, B. J. Matthews, and W. B. Grueber (2009)
Development 136, 1049-1061
   Abstract »    Full Text »    PDF »
Endodomain Diversity in the Drosophila Dscam and Its Roles in Neuronal Morphogenesis.
H.-H. Yu, J. S. Yang, J. Wang, Y. Huang, and T. Lee (2009)
J. Neurosci. 29, 1904-1914
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882