Regulation of low affinity neurotrophin receptor (p75^NTR) by early growth response (Egr) transcriptional regulators

The low affinity neurotrophin receptor p75^NTR is a multifunctional receptor with important roles in neurotrophin signaling, axon outgrowth, and oligodendroglia and neuron survival. It is transcriptionally regulated with spatial and temporal precision during nervous system development, injury and regeneration. Very little is known about how p75^NTR expression is dynamically regulated but it is likely to influence how p75^NTR signals in particular cellular contexts. Here, we identify the early growth response (Egr) transcriptional regulators, Egr1 and Egr3, as direct modulators of p75^NTR gene expression. Egr1 and Egr3 bind and transactivate the p75^NTR promoter in vitro and in vivo, using distinct response elements on the p75^NTR promoter. Consistent with these results, p75^NTR expression is greatly diminished in muscle spindle stretch receptors and in peripheral nerve Schwann cells in Egr gene deficient mice. Taken together, the results elucidate a novel mechanism whereby Egr proteins can directly modulate p75^NTR expression and signaling in vivo.