The role of early growth response transcriptional regulators in neurotrophin signaling and sympathetic nervous system development

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Early growth response genes (Egr1-4) are induced as immediate early genes by a variety of extracellular stimuli that influence cellular growth and differentiation. Egr transcriptional regulators modulate gene expression by binding to Egr response elements (ERE) in target genes. In this study, the low affinity p75 neurotrophin receptor (p75NTR) was identified as a target gene regulated by Egr transcriptional regulators. Both Egr1 and Egr3 were found to bind and transactivate the p75NTR promoter in vitro and in vivo, by using distinct EREs on p75NTR promoter. In the absence of Egr1 and Egr3 (Egr1/3 DKO) in vivo, p75NTR expression was greatly diminished in muscle spindle mechanoreceptors and in peripheral nerve Schwann cells. Interestingly, abnormally thin peripheral myelin was seen in Egr 1/3 DKO sciatic nerves, a phenotypic characteristic of mice lacking p75NTR. Therefore, these results suggest a novel mechanism that Egr proteins can directly modulate p75NTR function in vivo. Previous studies suggest that Egr1 and Egr3 may play redundant roles in sympathetic neuron development. To further investigate the cooperative roles of Egr genes in sympathetic neuron development in vivo, two transgenic mice and one knock-in mouse were generated. To visualize axon outgrowth and target tissue innervation of sympathetic neurons, DbH-taulacZ reporter mice were generated, in which taulacZ fusion protein was expressed in sympathetic neurons using a human dopamine beta-hydroxylase (hDbH) promoter. Beta-galactosidase histochemistry revealed that the fusion protein labeled almost all the sympathetic neurons and their axons innervating target organs. The reporter mice were used to characterize the sympathetic nervous system defects in Egr3-/- mice. To avoid the fertility-associated phenotypes of Egr-deficient mice, I utilized a dominant negative Egr (dnEgr) molecule to block Egr-mediated transcription in sympathetic neurons. DbH-dnEgr-IRES-taulacZ transgenic mice are embryonic lethal, perhaps due to sympathetic axon outgrowth defects. To conditionally express the dnEgr molecule in sympathetic neurons, Rosa26-dnEgr (RdnE) knock-in mice were generated and bred with DbH-nlsCre-IRES-taulacZ transgenic mice, in which nuclear-localized Cre recombinase (nlsCre) and taulacZ fusion protein were expressed in sympathetic neurons under the control of the hDbH promoter. The effect of the dnEgr molecule on sympathetic neuron development will be evaluated.

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  • 08/02/2018
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