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

Thomas G Mcwilliams,Laura Howard,Sean Wyatt,Alun M Davies

doi:10.1016/j.celrep.2015.02.016

Abstract

SummaryThe 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.

Highlights

Neurotrophic theory provides an explanation for how the target tissues of neuronal populations in the developing peripheral nervous system control their innervation
Neuronal autocrine signaling is difficult to reconcile with neurotrophic theory because it is not clear how autonomous signaling loops in neurons could contribute to the establishment of distinctive patterns of tissue innervation
Autocrine CD40 Reverse Signaling Enhances nerve growth factor (NGF)-Promoted Axon Growth The co-expression of CD40L and CD40 raised the possibility of autocrine signaling. To test this possibility and to ascertain how autocrine signaling might influence superior cervical ganglion (SCG) neuron development, we studied the effects of blocking the interaction of CD40L and CD40 using function-blocking antibodies and quantified neuronal survival and neurite growth

Summary

Introduction

Neurotrophic theory provides an explanation for how the target tissues of neuronal populations in the developing peripheral nervous system control their innervation. The basic idea is that tissues synthesize just the right amount of a neurotrophic factor to support the survival of the required number of innervating neurons and promote the growth and branching of their axons within the tissue. We demonstrate that CD40 autocrine signaling enhances NGF-promoted axonal growth and branching, is regulated by the level of NGF in targets, and exerts regional effects on innervation density in vivo. These findings resolve the long-standing conundrum of neuronal autocrine signaling by uncovering a mechanism of differential regulation of autocrine signaling within neuronal populations, resulting in specific regional effects on tissue innervation

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Discussion

Conclusion