Fig. 6.

Model for the interactions between p75NTR and TNFR1-TNFα in the regulation of axon development.

Activation of membrane-bound TNFα by either sTNFR1 or sTNFR2 promotes both axon growth rate and branching, leading to an increase in overall axon complexity. Conversely, membrane-bound TNFR1 may be activated by soluble TNFα, suppressing axon growth and branching, thereby reducing axon complexity. Pro-growth signaling through the former pathway is dominant, such that loss of either TNFα or both TNFR1 and TNFR2 results in catastrophic loss of axon complexity. p75NTR mediates a reduction in axon complexity and functionally antagonizes the pro-growth TNFR1-TNFα signaling axis. As such, loss of p75NTR results in exuberant axon branching, which is abrogated upon subsequent loss of either TNFR1 or TNFα. While p75NTR requires the presence of TNFR1 to suppress axon growth and branching in response to BDNF, TNFR1 displays no such dependence. This figure was created with Biorender.com and exported under a paid subscription.