Retrograde control of sympathetic neuron-satellite glia interactions by target-derived NGF signaling

Satellite glial cells (SGCs) are the major glial cells in sympathetic ganglia contacting neuronal cell bodies. The intimate association of SGCs with sympathetic neurons ideally positions these glia as critical regulators of neuronal homeostasis, architecture, and function. However, how these neuron-glia interactions are established remains unclear. Here, we find a contact-mediated pathway triggered by retrograde signaling from innervated sympathetic targets that underlies neuron-SGC interactions, neuronal morphology, and functional output. We show that neuronal expression of a transmembrane protein, Delta/Notch-like EGF-related receptor (DNER), is dependent on signaling by target-derived nerve growth factor (NGF). Neuronal DNER deletion disrupts neuron-SGC contacts and results in aberrant neuronal morphology, including decreased soma size and hyper-innervation of targets in mice. DNER mutant neurons have elevated activity, and mice lacking neuronal DNER exhibit increased heart rate and thermogenesis, indicative of enhanced sympathetic tone. These results suggest a mechanism whereby innervated targets control assembly of functional neuron-glia units in the sympathetic nervous system.