Regulation of Autocrine Signaling in Subsets of Sympathetic Neurons Has Regional Effects on Tissue Innervation

The regulation of innervation by target-derived factors like nerve growth factor (NGF) is the cornerstone of neurotrophic theory. Whereas autocrine signaling in neurons affecting survival and axon growth has been described, it is difficult to reconcile autocrine signaling with the idea that targets control their innervation. Here, we report that an autocrine signaling loop in developing mouse sympathetic neurons involving CD40L (TNFSF5) and CD40 (TNFRSF5) selectively enhances NGF-promoted axon growth and branching, but not survival, via CD40L reverse signaling. Because NGF negatively regulates CD40L and CD40 expression, this signaling loop operates only in neurons exposed to low levels of NGF. Consequently, the sympathetic innervation density of tissues expressing low NGF is significantly reduced in CD40-deficient mice, whereas the innervation density of tissues expressing high levels of NGF is unaffected. Our findings reveal how differential regulation of autocrine signaling in neurons has region-specific effects on axon growth and tissue innervation. [Display omitted] •CD40/CD40L autocrine signaling enhances NGF-promoted sympathetic axon growth•NGF negatively regulates CD40 and CD40L levels in developing sympathetic neurons•Accordingly, CD40/CD40L signaling only enhances axon growth at low levels of NGF•Innervation of tissues expressing low NGF levels is disrupted in CD40 knockout mice McWilliams et al. report that CD40/CD40L autocrine signaling in developing sympathetic neurons promotes axon growth. Because NGF negatively regulates CD40/CD40L expression, this autocrine-signaling loop operates only in neurons innervating low-NGF-expressing tissues, which are hypoinnervated in CD40 knockout mice. This reveals how autocrine signaling differentially regulates tissue innervation.