A Sympathetic Neuron Autonomous Role for Egr3-Mediated Gene Regulation in Dendrite Morphogenesis and Target Tissue Innervation

Abstract

Egr3 is a nerve growth factor (NGF)-induced transcriptional regulator that is essential for normal sympathetic nervous system development. Mice lacking Egr3 in the germline have sympathetic target tissue innervation abnormalities and physiologic sympathetic dysfunction similar to humans with dysautonomia. However, since Egr3 is widely expressed and has pleiotropic function, it has not been clear whether it has a role within sympathetic neurons and if so, what target genes it regulates to facilitate target tissue innervation. Here, we show that Egr3 expression within sympathetic neurons is required for their normal innervation since isolated sympathetic neurons lacking Egr3 have neurite outgrowth abnormalities when treated with NGF and mice with sympathetic neuron-restricted Egr3 ablation have target tissue innervation abnormalities similar to mice lacking Egr3 in all tissues. Microarray analysis performed on sympathetic neurons identified many target genes deregulated in the absence of Egr3, with some of the most significantly deregulated genes having roles in axonogenesis, dendritogenesis, and axon guidance. Using a novel genetic technique to visualize axons and dendrites in a subpopulation of randomly labeled sympathetic neurons, we found that Egr3 has an essential role in regulating sympathetic neuron dendrite morphology and terminal axon branching, but not in regulating sympathetic axon guidance to their targets. Together, these results indicate that Egr3 has a sympathetic neuron autonomous role in sympathetic nervous system development that involves modulating downstream target genes affecting the outgrowth and branching of sympathetic neuron dendrites and axons.

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

“…Reverse transcriptase (RT)-PCR and qPCR were performed as previously (Albert et al, 2005;Quach et al, 2013) and are outlined in detail in supplementary methods (see supplementary material).…”

“…In vivo ganglion neuron counts and primary neuron culture and cell survival Neuron counts and primary neuron culture were performed as previously described (Quach et al, 2013). Primary neuron survival was performed as previously described and detailed as previously described (Eldredge et al, 2008).…”

Molecular basis of dendritic atrophy and activity in stress susceptibility

“…18–23 Additionally, EGR molecules are critically involved in stabilization of neuronal plasticity, neuron outgrowth and cytoskeletal regulation. 16,21,23–25 Chronic stress mediates widespread adaptations to synaptic density and dendritic arbor. 26 Stress-induced impairment in structural and synaptic alterations as well as their molecular underpinnings have been extensively studied in limbic excitatory brain regions, 26–28 but there is minimal information into these mechanisms in GABAergic neurons, including MSN subtypes.…”

Intrinsic Axonal Growth and the Drive for Regeneration

“…The zinc finger-containing immediate early gene transcription factor Egr3 has a demonstrated role in axon growth (Eldredge et al, 2008; Quach et al, 2013). Interestingly, Egr3 null mice have degenerating muscle spindles, (Tourtellotte and Milbrandt, 1998) which fail to express NT-3, which results in type Ia afferents failing to reach their targets in the muscle spindle (Chen et al, 2002).…”

“…Egr3 is also required for proper innervation of salivary glands and heart where NGF and NT-3 expression persist in the absence of Egr3 suggesting that Egr3 regulates axon growth via neurotrophin-independent factors in these contexts. More recent studies have demonstrated a role for Egr3 in sympathetic neuron axon branching and dendritic morphology (Quach et al, 2013). …”