Egr3 is a Novel Transcriptional Regulator of Sympathetic Nervous System Development and Function

Laurie Christine Eldredge

doi:https://doi.org/10.21985/N27T7M

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Egr3 is a Novel Transcriptional Regulator of Sympathetic Nervous System Development and Function

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Early Growth Response genes (Egr1-4) are transcriptional mediators of signals governing growth and differentiation. In sympathetic neuron-derived cell lines, Egr1 is induced by NGF signaling, which is required for sympathetic neuron survival, differentiation and target organ innervation. In the absence of identifiable sympathetic defects in Egr1-deficient mice, we investigated the role of a closely related Egr family member Egr3 in NGF-mediated aspects of sympathetic neuron development. Here, we show that Egr3 expression is coupled to neurotrophin signaling in vitro and in vivo. Moreover, in Egr3-deficient mice, approximately 1/3 of sympathetic neurons die after birth due to increased apoptosis. These neuronal deficits manifest as decreased sympathetic innervation in a variety of target tissues as well as disrupted end-organ physiology. Indeed, loss of Egr3 results in ptosis as well as abnormal cardiac and circadian physiologies. Detailed examination of Egr3-deficient mice revealed reduced axon arborization within a variety of target tissues. 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 trophic support since Egr3-deficient neurons do not have NGF-dependent survival defects in vitro. In support of this hypothesis, Egr3/Bax double homozygous mutant mice retain target innervation defects when sympathetic neuron death is prevented. Therefore, Egr3 plays a critical and novel role in differentiating sympathetic neurons, presumably inducing expression of genes involved in neurite branching or extension. Furthermore, 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.

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