Mice lacking the transcriptional regulator Egr3 have Nerve Growth Factor (NGF) signaling defects and profound sympathetic dysautonomia.

Early growth response (Egr) transcriptional regulators (Egr1–4) are essential mediators of cellular growth and differentiation. In sympathetic neuron‐derived cell lines, some Egr proteins are induced by NGF signaling, which is required for sympathetic neuron survival, differentiation and target organ innervation. Whether Egr proteins have any role as downstream mediators of NGF signaling in the sympathetic nervous system is not known. Here, we show that Egr3 expression is coupled to NGF signaling in sympathetic neurons in vitro and in vivo. Moreover, in Egr3‐deficient mice, approximately 1/3 of sympathetic neurons die after birth due to increased apoptosis. Consequently, some target tissues have severe sympathetic innervation defects and many of the remaining sympathetic axons appear to have defects in arborization. These results suggest that sympathetic neuron death in Egr3‐deficient mice may be due to axon outgrowth defects and insufficient access to target tissue‐derived NGF since Egr3‐deficient neurons do not have NGF‐dependent survival defects in vitro. Remarkably, Egr3‐deficient mice have a sympathetic dysautonomia that resembles human disease, raising the possibility that Egr3 has an important role in human sympathetic nervous system development and/or sympathetic neuron degeneration. Support: NIH and HHMI.