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TNFα reverse signaling promotes sympathetic axon growth and target innervation

Nature Neuroscience volume 16, pages 865–873 (2013)Cite this article

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Abstract

Reverse signaling via members of the tumor necrosis factor (TNF) superfamily controls multiple aspects of immune function. Here we document TNFα reverse signaling in the nervous system to our knowledge for the first time and show that it has a crucial role in establishing sympathetic innervation. During postnatal development, sympathetic axons express TNFα as they grow and branch in their target tissues, which in turn express TNF receptor 1 (TNFR1). In culture, soluble forms of TNFR1 act directly on postnatal sympathetic axons to promote growth and branching by a mechanism that depends on membrane-integrated TNFα and on downstream activation of ERK. Sympathetic innervation density is substantially lower in several tissues in postnatal and adult mice lacking either TNFα or TNFR1. These findings reveal that target-derived TNFR1 acts as a reverse-signaling ligand for membrane-integrated TNFα to promote growth and branching of sympathetic axons.

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Figure 1: Expression of TNFα and TNFR1 in developing SCG neurons and their targets.
Figure 2: TNFR1-promoted TNFα reverse signaling enhances neurite growth from SCG P0 neurons.
Figure 3: TNFR1-Fc acts locally on SCG axons to enhance growth over a window of postnatal development.
Figure 4: Reduced sympathetic innervation density in Tnf−/− (a–d) and Tnfrsf1a−/− mice (e–h).
Figure 5: Sympathetic innervation density in adult Tnf−/− and Tnfrsf1a−/− mice, and nerve fiber branching in P10 Tnf−/− and Tnfrsf1a−/− mice.
Figure 6: Cytosolic Ca2+ elevation and ERK1 and ERK2 activation are required for TNFR1-Fc–promoted neurite growth.

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Acknowledgements

We thank M. White for providing RNA samples and K. Fox (Cardiff University), A. Dick (Bristol University) and the late S. Korsmeyer for providing Tnf, Tnfrsf1a and Bax mutant mice, respectively. This work was supported by a Wellcome Trust grant (grant no. 085984). C.O. was supported by a grant from the Fundação para a Ciência e a Tecnologia. C.E. was supported by a studentship from the Neuroscience and Mental Health Research Institute of Cardiff University.

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  1. Thomas Vizard

    Present address: Present address: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.,

Authors and Affiliations

  1. Division of Molecular Biosciences, School of Biosciences, Cardiff University, Cardiff,, UK

    Lilian Kisiswa, Catarina Osório, Clara Erice, Thomas Vizard, Sean Wyatt & Alun M Davies

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Contributions

L.K. conducted the majority of the cell culture experiments, quantified submandibular gland and iris innervation and did the western blot analysis. C.O. quantified nasal tissue and adult submandibular gland innervation. C.E. undertook the immunocytochemical and immunohistochemical localization of TNFα and TNFR1 and the whole-mount studies. T.V. contributed to studies of iris innervation. S.W. carried out the QPCR. L.K. and A.M.D. wrote the manuscript. A.M.D. supervised the project.

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Correspondence to Alun M Davies.

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Kisiswa, L., Osório, C., Erice, C. et al. TNFα reverse signaling promotes sympathetic axon growth and target innervation. Nat Neurosci 16, 865–873 (2013). https://doi.org/10.1038/nn.3430

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