Editors' ChoiceNeuronal Development

Reversing Roles for Innervation

Sci. Signal.  02 Jul 2013:
Vol. 6, Issue 282, pp. ec149
DOI: 10.1126/scisignal.2004467

The extension and innervation of axons in the nervous system are guided by proteins and growth factors secreted by target tissues. Kisiswa et al. found that a reverse signaling mechanism involving tumor necrosis factor (TNF) receptor type 1 (TNFR1) and TNFα occurs during sympathetic innervation in postnatal mice. Transcript abundance of both Tnf and Tnfrsf1a in mouse superior cervical ganglion (SCG) gradually increased from embryonic day 13 (E13) to postnatal day 5 (P5), followed by a decline into adulthood. Tnf–/– or Tnfrsf1a–/– mice had a lower density of sympathetic innervation than did wild-type mice. In situ or in cultures from P0 wild-type mice, TNFα was abundant in the cell bodies (or soma) and branching structures (neurite arbors and fiber bundles) of SCG neurons, whereas TNFR1 was detected only in soma. Several SCG target tissues were positive for only TNFR1 or both TNFR1 and TNFα, but sympathetic fibers therein were positive for only TNFα. The length and number of neurite arbors in SCG neurons cultured from P0 or P5 wild-type, Tnf+/–, or TNFR1-deficient mice were increased by treatment with chimeric or soluble TNFR1 (TNFR1-Fc or sTNFR1, respectively), which bind TNFα and, in immune cells, stimulate a “reverse” signal. Neither TNFR1-Fc nor sTNFR1 had an affect in cultures derived from Tnf–/– mice or P10 wild-type mice, and pretreatment of the cultures with TNFα-converting enzyme (TACE, which cleaves and releases membrane-integrated TNFα) inhibited the effects of TNFR1-Fc on neurite length and numbers, suggesting that the TNFR1-Fc and sTNFR1 may be generating a signal through the membrane-bound TNFα on the axons to stimulate growth and branching. Axons exposed locally to TNFR1-Fc in a compartmental culture system showed increased growth and branching, whereas those exposed to soluble TNFα showed no change, further supporting the hypothesis that TNFR1 can stimulate signaling through axonal membrane-bound TNFα. Furthermore, TNFR1-Fc induced the phosphorylation of ERK1 (extracellular signal–regulated kinase 1) and ERK2 (ERK1/2) in axons in a TNFα- and intracellular calcium–dependent manner. Pharmacological inhibition of ERK1/2 or treatment with a calcium chelator inhibited TNFR1-Fc–induced growth and branching in cultured P0 wild-type SCG neurons. Together, the findings suggested that TNFR1, which is present in target tissues, acts as a ligand for membrane-bound TNFα in axons to promote the innervation of postnatal sympathetic neurons through a calcium and ERK-dependent mechanism.

L. Kisiswa, C. Osório, C. Erice, T. Vizard, S. Wyatt, A. M. Davies, TNFα reverse signaling promotes sympathetic axon growth and target innervation. Nat. Neurosci. 16, 865–873 (2013). [PubMed]