Neurotrophin receptors corresponding to vertebrate Trk, p75NTR or Sortilin have not been identified in Drosophila, thus it is unknown how neurotrophism may be implemented in insects. Two Drosophila neurotrophins, DNT1 and DNT2, have nervous system functions, but their receptors are unknown. The Toll receptor superfamily has ancient evolutionary origins and a universal function in innate immunity. Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. DNT1 (also known as NT1 and spz2) and DNT2 (also known as NT2 and spz5) interact genetically with Toll-6 and Toll-7, and DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously and are distributed in vivo in domains complementary to or overlapping with those of Toll-6 and Toll-7. We conclude that in fruit flies, Tolls are not only involved in development and immunity but also in neurotrophism, revealing an unforeseen relationship between the neurotrophin and Toll protein families.
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We thank C. Arnot, J. Wen and M. Wheatley for advice; S. Jondhale, J. Ng and S. Quayle for technical help; S. Bishop and K. Kato for comments on the manuscript; A.J. Courey (University of California, Los Angeles), J.L. Imler (Institut de Biologie Moléculaire et Cellulaire, CNRS, Strasbourg), T. Ip (University of Massachusetts), J.M. Reichhart (Institut de Biologie Moléculaire et Cellulaire, CNRS, Strasbourg), S. Sanyal (Emory University), R. Baines (University of Manchester), M. Freeman (University of Oxford), K. Ito (University of Tokyo), A. Chiba (University of Miami), B. Pfeiffer (Janelia Farm), M. Landgraf (University of Cambridge), C. Basler (University of Zurich), H. Broihier (Case Western Reserve University), D. Ferrandon (CNRS, Strasbourg), the Bloomington Stock Center and Iowa Hybridoma Bank for reagents; the Birmingham Mass Spectrometry Facility (Birmingham Science City, Advantage West Midlands); and Len Packman for mass spectrometry and Edman sequencing in Cambridge. The LTQ Orbitrap Velos ETD mass spectrometer used in this research was obtained through the Birmingham Science City Translational Medicine: Experimental Medicine Network of Excellence project, with support from Advantage West Midlands (AWM). This work was funded by a UK Medical Research Council Career Establishment Grant (MRCG0200140) to A.H., Wellcome Trust project grant (WT094175/Z/10/Z) to A.H. and N.J.G., Wellcome Trust equipment grant (WT073228/Z/03/Z) to A.H., Wellcome Trust programme grant (WT081744MA) to N.J.G., European Union Marie Curie International Incoming Fellowship (PIIF-GA-2010-274193-NPN) to J.S.W., UK Medical Research Council studentship to G.M. and Brunei government studentship to M.A.L.
The authors declare no competing financial interests.
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McIlroy, G., Foldi, I., Aurikko, J. et al. Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nat Neurosci 16, 1248–1256 (2013). https://doi.org/10.1038/nn.3474
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