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Dscam guides embryonic axons by Netrin-dependent and -independent functions
Gracie L. Andrews1,
W. Todd Farmer1,
Michael A. Berberoglu1,
George C. Fernandez3,
Grant S. Mastick1,
Frédéric Charron2,4, and
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,
Author for correspondence (e-mail:
Accepted for publication 22 September 2008.
Developing axons are attracted to the CNS midline by Netrinproteins and
other as yet unidentified signals. Netrin signalsare transduced in part by
Frazzled (Fra)/DCC receptors. Geneticanalysis in Drosophila
indicates that additional unidentifiedreceptors are needed to mediate the
attractive response to Netrin.Analysis of Bolwig's nerve reveals that
Netrin mutants havea similar phenotype to Down Syndrome Cell
Adhesion Molecule(Dscam) mutants. Netrin and
Dscam mutants display dose sensitiveinteractions, suggesting that
Dscam could act as a Netrin receptor.We show using cell overlay assays that
Netrin binds to fly andvertebrate Dscam, and that Dscam binds Netrin with the
sameaffinity as DCC. At the CNS midline, we find that Dscam andits
paralog Dscam3 act redundantly to promote midline crossing.
Simultaneousgenetic knockout of the two Dscam genes and the Netrin
receptorfra produces a midline crossing defect that is stronger than
theremoval of Netrin proteins, suggesting that Dscam proteins alsofunction
in a pathway parallel to Netrins. Additionally, overexpressionof
Dscam in axons that do not normally cross the midline isable to
induce ectopic midline crossing, consistent with anattractive receptor
function. Our results support the modelthat Dscam proteins function as
attractive receptors for Netrinand also act in parallel to Frazzled/DCC.
Furthermore, the resultssuggest that Dscam proteins have the ability to
respond to multipleligands and act as receptors for an unidentified midline
attractivecue. These functions in axon guidance have implications forthe
pathogenesis of Down Syndrome.
Key Words:Drosophila genetics Axon guidance Body patterning Cell migration Central nervous system Signal transduction
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