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Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in the Drosophila embryonic central nervous system
Rene R. Wouda,
Monique R. K. S. Bansraj,
Anja W. M. de Jong,
Jasprina N. Noordermeer*, and
Lee G. Fradkin*
Laboratory of Developmental Neurobiology, Department of Molecular and
Cell Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC,
Leiden, The Netherlands.
Authors for correspondence (e-mails:
Accepted for publication 5 May 2008.
Members of the RYK/Derailed family have recently been shownto regulate
axon guidance in both Drosophila and mammals byacting as Wnt
receptors. Little is known about how the kinaseactivity-deficient RYKs
transduce Wnt signals. Here, we showthat the non-receptor Src family tyrosine
kinases, SRC64B andSRC42A, are involved in WNT5-mediated signaling through
Derailedin the Drosophila embryonic central nervous system. Analysis
ofanimals lacking SRC64B and SRC42A reveals defects in commissureformation
similar to those observed in Wnt5 and derailed mutants.
Reductionsin SRC64B expression levels suppress a
Wnt5/derailed-dependentdominant gain-of-function phenotype,
and increased levels ofeither SRC64B or SRC42A enhance
Wnt5/derailed-mediated axoncommissure switching. Derailed
and SRC64B form a complex, whichcontains catalytically active SRC64B, the
formation or stabilityof which requires SRC64B kinase activity. Furthermore,
Derailedis phosphorylated in a SRC64B-dependent manner and coexpressionof
Derailed and SRC64B results in the activation of SRC64B.The mammalian
orthologs of Derailed and SRC64B also form complexes,suggesting that Src
roles in RYK signaling are conserved. Finally,we show that coexpression of
WNT5 and Derailed has no apparenteffect upon TCF/LEF-dependent transcription,
suggesting thatthe WNT5/Derailed signaling pathway is unlikely to directly
regulatecanonical Wnt pathway targets. Together, these findings indicatethat
the Src family kinases play novel roles in WNT5/Derailed-mediated
Key Words: Axon guidance RYK Src family kinase Wnt Signal transduction
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Receptor Tyrosine Kinases in Drosophila Development.