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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionNeurotrophic 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. Neurotrophic theory is endorsed by a large body of work on nerve growth factor (NGF), the first neurotrophic factor to be identified, and has been corroborated by studies of other members of the NGF family of neurotrophins and by other neurotrophic factors (, , ). In addition to target-derived signals, autocrine signaling in neurons involving neurotrophins and other secreted signaling molecules has been shown to affect neuronal survival, axon growth, and other aspects of neuronal development and function (, , , , ). However, 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.From a PCR screen to identify novel regulators of neuronal survival and axon growth, we detected expression of transcripts encoding CD40L (TNFSF5), a member of the tumor necrosis factor superfamily (TNFSF), and CD40 (TNFRSF5), a memberof the TNF receptor superfamily (TNFRSF), in the experimentally tractable sympatheticneurons of the mouse superior cervical ganglion (SCG) at the stage when the axons ofthese neurons are ramifying extensively in their target tissues. CD40L and CD40 areprominently expressed in the immune system, where they play a central role in thegeneration of immune responses and the pathogenesis of autoimmune disease(, ). Whereas there is some evidence for theappearance of a neurodegenerative phenotype in aged CD40 knockout mice (), CD40 and CD40Lare not known to play any role in neural development. We demonstrate that CD40autocrine signaling enhances NGF-promoted axonal growth and branching, is regulatedby the level of NGF in targets, and exerts regional effects on innervation densityin vivo. These findings resolve the long-standing conundrum of neuronal autocrinesignaling by uncovering a mechanism of differential regulation of autocrine signalingwithin neuronal populations, resulting in specific regional effects on tissueinnervation.