Neuregulin‐4 contributes to the establishment of cutaneous sensory innervation

Recent work has shown that neuregulin‐4 (NRG4) is a physiological regulator of the growth of sympathetic axons and CNS dendrites in the developing nervous system. Here, we have investigated whether NRG4 plays a role in sensory axon growth and the establishment of cutaneous sensory innervation. Imaging early nerve fibers in the well‐characterized cutaneous trigeminal territory, the brachial plexus, and thorax revealed very marked and highly significant decreases in nerve fiber length and branching density in Nrg4 (−/−) embryos compared with Nrg4 (+/+) littermates. NRG4 promoted neurotrophin‐independent sensory axon growth from correspondingly early trigeminal ganglion and DRG neurons in culture but not from enteroceptive nodose ganglion neurons. High levels of Nrg4 mRNA were detected in cutaneous tissues but not in sensory ganglia. Our findings suggest that NRG4 is an important target‐derived factor that participates in the establishment of early cutaneous sensory innervation.