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Specificity of sensory–motor connections encoded by Sema3e–Plxnd1 recognition

Nature volume 459, pages 842–846 (2009)Cite this article

Abstract

Spinal reflexes are mediated by synaptic connections between sensory afferents and motor neurons1,2,3. The organization of these circuits shows several levels of specificity. Only certain classes of proprioceptive sensory neurons make direct, monosynaptic connections with motor neurons4. Those that do are bound by rules of motor pool specificity: they form strong connections with motor neurons supplying the same muscle, but avoid motor pools supplying antagonistic muscles1,5,6,7. This pattern of connectivity is initially accurate and is maintained in the absence of activity8, implying that wiring specificity relies on the matching of recognition molecules on the surface of sensory and motor neurons. However, determinants of fine synaptic specificity here, as in most regions of the central nervous system, have yet to be defined. To address the origins of synaptic specificity in these reflex circuits we have used molecular genetic methods to manipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here that a recognition system involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 (Plxnd1) by proprioceptive sensory neurons, is a critical determinant of synaptic specificity in sensory–motor circuits in mice. Changing the profile of Sema3e–Plxnd1 signalling in sensory or motor neurons results in functional and anatomical rewiring of monosynaptic connections, but does not alter motor pool specificity. Our findings indicate that patterns of monosynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signalling.

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Figure 1: Sema3e marks cutaneous maximus motor neurons, and Plxnd1 marks proprioceptive neurons.
Figure 2: Loss of Sema3e or Plxnd1 function perturbs monosynaptic specificity.
Figure 3: Increase in vGlut1 sensory contacts with cutaneous maximus motor neurons in Sema3e mutant mice.
Figure 4: Ectopic expression of Sema3e in motor neurons prevents monosynaptic connectivity.
Figure 5: Regulation of synaptic specificity by repellent Sema3e–Plxnd1 signalling.

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Acknowledgements

We thank D. Ladle for help in analysis of electrophysiological data, J. Livet and C. Henderson for discussions, and P. Schwarb, A. Ponti and M. Stadler for help in image and statistical analysis. M. Mendelsohn, J. Kirkland and B. Han helped in the generation of Plxnd1cond mice and J. F. Spetz, P. Kopp and B. Kuchemann in the generation of Sema3e mutant and MN::Sema3e mice. R. Axel, P. Caroni, E. Frank, A. Hantman, C. Henderson, D. Ladle and A. Luethi provided comments on the manuscript. E.P.-V., M.S. and S.A. are supported by the Swiss National Science Foundation, NCCR Frontiers in Genetics, the Kanton Basel-Stadt, EU Framework Program 7 and the Novartis Research Foundation. Y.Y. is supported by NIH grant RO1NS065048. T.M.J. is an HHMI Investigator, and is supported by grants from NINDS, EU Framework Program 7, Project ALS, The Harold and Leila Mathers Foundation, and The Wellcome Trust.

Author Contributions E.P.-V., M.S. and Y.Y. made critical primary contributions to this study. E.P.-V. performed physiological analysis of sensory–motor connectivity and tracing experiments in wild-type and mutant mice. M.S. participated in Sema3e and Plxnd1 subpopulation assignment, anatomical analyses of sensory–motor organization and generated Sema3enlz/nlz and MN::Sema3e mice. Y.Y. found that Plxnd1 is expressed by subsets of proprioceptive sensory neurons and generated Plxnd1cond mice. T.M.J. and S.A. initiated complementary aspects of this project, analysed data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Cell Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland, and Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland

    Eline Pecho-Vrieseling, Markus Sigrist & Silvia Arber

  2. Departments of Neuroscience and Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Kavli Institute for Brain Science, Columbia University, New York, USA

    Yutaka Yoshida & Thomas M. Jessell

  3. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA,

    Yutaka Yoshida

Authors
  1. Eline Pecho-Vrieseling
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  3. Yutaka Yoshida
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  4. Thomas M. Jessell
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  5. Silvia Arber
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Corresponding authors

Correspondence to Thomas M. Jessell or Silvia Arber.

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Pecho-Vrieseling, E., Sigrist, M., Yoshida, Y. et al. Specificity of sensory–motor connections encoded by Sema3e–Plxnd1 recognition. Nature 459, 842–846 (2009). https://doi.org/10.1038/nature08000

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