Sympathetic dysautonomia despite the absence of sympathetic neuron loss in Egr3‐deficient mice

Abstract

The sympathetic nervous system (SNS) is essential for tissue and organ homeostasis. Despite the fact that it is the target of a wide variety of congenital and degenerative diseases, the mechanisms involved in sympathetic neuron differentiation and target tissue innervation are still very poorly characterized. Sympathetic neurons depend upon target tissue‐derived trophic factors such as nerve growth factor (NGF) for survival and differentiation, but the downstream signaling molecules that regulate new gene expression have not been fully defined. We recently identified the NGF‐regulated transcription factor Egr3 as an essential mediator of normal SNS development. Egr3‐deficient mice can survive to adulthood but they have profound physiologic dysautonomia reminiscent of human disease. The dysautonomia is associated with sympathetic neuron loss and abnormal target tissue innervation. Thus, it has not been clear whether Egr3 is primarily involved in gene regulation related to sympathetic neuron survival, differentiation or both. To examine whether Egr3 has a direct role in sympathetic neuron survival, Egr3 knockout mice were mated to mice lacking the pro‐apoptotic molecule Bax. We found that both physiologic and Egr3‐dependent sympathetic neuron death was completely inhibited in Egr3−/−:Bax−/− double knockout mice, yet the mice still had dysautonomia and target tissue innervation defects. These results demonstrate that Egr3 has an essential role in sympathetic axon outgrowth and target tissue innervation that is independent of any role it may have in sympathetic neuron survival. Moreover, the results reaffirm the concept that human dysautonomias, which are virtually always associated with neuron loss, are not necessarily caused by primary defects in neuron survival. Support: NIH and HHMI.