Egr3 is a transcriptional regulator required for normal target tissue innervation during sympathetic nervous system development

Abstract

Nerve Growth Factor (NGF) is a target tissue‐derived neurotrophin that is essential for normal sympathetic nervous system (SNS) development. Egr3 is regulated by NGF signaling and in Egr3‐deficient mice sympathetic neuron loss and target tissue innervation abnormalities lead to physiologic dysautonomia. It has not been clear to what extent Egr3 regulates sympathetic neuron survival or target tissue innervation. Here, we show that Egr3 has no effect on NGF‐dependent neuron survival or neurite outgrowth in vitro, but that inhibition of sympathetic neuron death in the absence of Egr3 in vivo leads to target tissue innervation abnormalities. To better understand the mechanism of Egr3 action, microarray analysis was used to identify potential target genes regulated by Egr3 in developing sympathetic neurons. We identified two potentially interesting genes, Hs3st2 and Esd which were confirmed to be downregulated in the absence of Egr3 and the promoters were confirmed to be transactivated by Egr3. Hs3st2 and Esd may be involved in the modification of carbohydrate molecules located on cell surface membranes, and several studies indicate that carbohydrate moieties can be essential for normal axon guidance and branching. Thus, Egr3 may regulate some target genes involved in the modification of cell surface molecules that have a role in sympathetic terminal axon invasion and ramification within target tissues.