A requirement for filopodia extension toward Slit during Robo-mediated axon repulsion.
Axons navigate long distances through complex 3D environments to interconnect the nervous system during development. Although the precise spatiotemporal effects of most axon guidance cues remain poorly characterized, a prevailing model posits that attractive guidance cues stimulate actin polymerization in neuronal growth cones whereas repulsive cues induce actin disassembly. Contrary to this model, we find that the repulsive guidance cue Slit stimulates the formation and elongation of actin-based filopodia from mouse dorsal root ganglion growth cones. Surprisingly, filopodia form and elongate toward sources of Slit, a response that we find is required for subsequent axonal repulsion away from Slit. Mechanistically, Slit evokes changes in filopodium dynamics by increasing direct binding of its receptor, Robo, to members of the actin-regulatory Ena/VASP family. Perturbing filopodium dynamics pharmacologically or genetically disrupts Slit-mediated repulsion and produces severe axon guidance defects in vivo. Thus, Slit locally stimulates directional filopodial extension, a process that is required for subsequent axonal repulsion downstream of the Robo receptor.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239.
Russell E
RE
McConnell
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 01239.
J
J
Edward van Veen
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239.
Marina
M
Vidaki
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 01239.
Adam V
AV
Kwiatkowski
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239.
Aaron S
AS
Meyer
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 01239 fgertler@mit.edu.
Frank B
FB
Gertler
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D002633:Chemotaxis; D047108:Embryonic Development; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011554:Pseudopodia / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D000097905:Roundabout Proteins
D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; C120566:slit protein, vertebrate