A Neurotrophin Signaling Cascade Coordinates Sympathetic Neuron Development through Differential Control of TrkA Trafficking and Retrograde Signaling

Abstract

A fundamental question in developmental biology is how a limited number of growth factors and their cognate receptors coordinate the formation of tissues and organs endowed with enormous morphological complexity. We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT-3 cannot. Interestingly, final target-derived NGF promotes expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT-3. We propose that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TrkA internalization, trafficking, and retrograde axonal signaling.

Stress-induced remodeling of lymphoid innervation

“…The density of peripheral sympathetic innervation is governed in large part by target organ expression of neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) (Carlson, Albers et al 1995;Kuruvilla, Zweifel et al 2004;Bronzetti, Artico et al 2006). Consistent with the hypothesis that stress increases lymphoid tissue innervation via increased neurotrophic support, we found increased expression of both NGF and BDNF in lymph nodes from animals socialized under unstable conditions.…”

Biallelic SEMA3A defects cause a novel type of syndromic short stature

“…Sema3a has been identified as the chemorepellent agent inducing growth cone collapse and repelling sympathetic axons in the heart, as opponent of NGF, reported to be required for active sympathetic axon growth and innervation in the heart [Ieda et al, 2004[Ieda et al, , 2007Kuruvilla et al, 2004]. It could be shown that mice targeted with Sema3a or those overexpressing the gene display sudden cardiac death or lethal arrhythmias due to disruption of innervation patterning.…”

Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample

“…Of these, the genes encoding ionotropic Nmethyl D-aspartate glutamate receptor subunit 2B (GRIN2B), neurotrophin 3 (NTF3), GABA-A receptor-associated protein-like protein 1 (GABARAPL1) and a cluster of subunits for a taste receptor represent plausible candidates for a future association study in view of their biological function(s) and the biochemical pathways involved in drug addiction. [46][47][48][49][50] Although several association studies have been conducted to investigate the association of NTF3 and GRIN2B with schizophrenia and alcohol dependence, the results have been inconclusive. [51][52][53][54] Regarding potential candidate genes from other regions, we will not discuss these in the present report because (1) they have been reported previously for possible association with nicotine and/or alcohol dependence in independent sample; (2) potential candidate genes for a few chromosomal regions were discussed in our recent report based on the AA sample; 20 and/or (3) a limited number of candidate genes are obvious on the basis of their functionality unless we are able to demonstrate their association experimentally, a consideration which is well beyond the scope of this report.…”