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Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS

Nature Neuroscience volume 16, pages 1248–1256 (2013)Cite this article

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Abstract

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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Figure 1: Toll-6 and Toll-7 are expressed in the CNS through all stages.
Figure 2: Identification of Toll-6 and Toll-7 cells in the locomotor circuit.
Figure 3: Toll-6 and Toll-7 are required for larval locomotion and motor-axon targeting.
Figure 4: Toll-6 and Toll-7 maintain neuronal survival.
Figure 5: Toll-6 and Toll-7 interact genetically with DNT2 and DNT1.
Figure 6: In vitro, cell culture and in vivo evidence that Toll-7 and Toll-6 bind DNT1 and DNT2.
Figure 7: The relative distributions of DNT1, 2 and Toll-7, 6, respectively, in vivo are consistent with their functions are ligand-receptor pairs.

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Acknowledgements

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.

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  1. Graham McIlroy and Istvan Foldi: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK

    Graham McIlroy, Istvan Foldi, Jill S Wentzell, Mei Ann Lim, Janine C Fenton & Alicia Hidalgo

  2. Department of Biochemistry, University of Cambridge, Cambridge, UK

    Jukka Aurikko & Nicholas J Gay

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Contributions

G.M., I.F., J.A., J.S.W., M.A.L., J.C.F. and A.H. performed experiments; A.H. and N.J.G. conceived and directed the project; A.H., N.J.G. and G.M. wrote the paper; all authors contributed to planning experiments and analyzing data and to discussions and improvements to the manuscript.

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Correspondence to Alicia Hidalgo.

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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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