Functionally Antagonistic Interactions between the TrkA and p75 Neurotrophin Receptors Regulate Sympathetic Neuron Growth and Target Innervation

Abstract

In this report, we provide evidence that NGF and BDNF have functionally antagonistic actions on sympathetic neuron growth and target innervation, with NGF acting via TrkA to promote growth and BDNF via p75NTR to inhibit growth. Specifically, in cultured sympathetic neurons that themselves synthesize BDNF, exogenous BDNF inhibits and function-blocking BDNF antibodies enhance process outgrowth. Both exogenous and autocrine BDNF mediate this effect via p75NTR because (1) BDNF does not inhibit growth of neurons lacking p75NTR, (2) function-blocking p75NTR antibodies enhance NGF-mediated growth, and (3) p75NTR-/- sympathetic neurons grow more robustly in response to NGF than do their wild-type counterparts. To determine the physiological relevance of this functional antagonism, we examined the pineal gland, a well defined sympathetic target organ. BDNF is present in the pineal gland during target innervation, and incoming sympathetic axons are p75NTR positive. Moreover, the pineal glands of BDNF+/- and BDNF-/- mice are hyperinnervated with sympathetic fibers, and tyrosine hydroxylase (TH) levels are elevated. Increased tyrosine hydroxylase is also observed in the BDNF+/- carotid artery, another sympathetic neuron target. Thus, BDNF, made by sympathetic neurons and/or their target organs, acts via p75NTR to antagonize NGF-mediated growth and target innervation, suggesting that sympathetic target innervation is determined by the balance of positively and negatively acting neurotrophins present in developing and potentially mature targets.

The Extracellular Domain of p75NTR Is Necessary to Inhibit Neurotrophin-3 Signaling through TrkA

“…Antagonistic interactions between the signaling pathways of Trk receptors and p75 NTR have been described (21,37,38). However, our finding that the extracellular domain of p75 NTR inhibited NT-3 signaling, whereas most of the cytoplasmic domain was dispensable, suggests that events occurring between the receptors on the plasma membrane and between their extracellular domains are critical for inhibiting NT-3 signaling through TrkA.…”

Reduced age‐related plasticity of neurotrophin receptor expression in selected sympathetic neurons of the rat

“…Similarly, sympathetic and sensory neurons exhibit reduced responsiveness to a mutated NGF protein with reduced binding to p75 but wildtype binding to trkA (Horton et al ., 1997). Activated p75 and trkA mediate positive growth responses to NGF in adult sympathetic neurons (Orike et al , 2001b) and are required for NGF uptake and retrograde transport in adult sympathetic neurons (Gatzinsky et al ., 2001), despite the possibility that p75, when activated alone, exerts negative effects on growth (Kohn et al ., 1999). In sympathetic neurons, NT3 appears also to act through trkA and through p75 rather than through its cognate receptor, trkC Dechant et al ., 1997).…”

Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: Potential implications for Rett syndrome

“…For example, while Trk receptors are essential for neuronal survival, p75 NTR have been implicated in neuronal apoptosis (Rabizadeh et al, 1993;Frade et al, 1996;Bamji et al, 1998;Miller and Kaplan, 2001). Second, p75 NTR signaling has been linked to the inhibition of axonal growth, an opposing effect to that of Trk receptors (Yeo et al, 1997;Kohn et al, 1999;Walsh et al, 1999;Yamashita et al, 1999). Third, while TrkB receptors have been shown to be critical for the role of BDNF in hippocampal long-term potentiation (LTP) (Minichiello et al, 1999;Minichiello et al, 2002;Xu et al, 2000), recent reports indicate that p75 NTR is necessary for the induction and/or expression of hippocampal long-term depression (LTD) (Rosch et al, 2005;Woo et al, 2005).…”