Transcytosis of TrkA leads to diversification of dendritic signaling endosomes

Abstract

The development of the peripheral nervous system relies on long-distance signaling from target organs back to the soma. In sympathetic neurons, this long-distance signaling is mediated by target derived Nerve Growth Factor (NGF) interacting with its axonal receptor, TrkA. This ligand receptor complex internalizes into what is commonly referred to as the signaling endosome which is transported retrogradely to the soma and dendrites to mediate survival signaling and synapse formation, respectively. The molecular identity of signaling endosomes in dendrites has not yet been determined. Here, we perform a detailed analysis of TrkA endosomal compartments and trafficking patterns. We find that signaling endosomes are not uniform but molecularly diversified into Rab7 (late endosome) and Rab11 (recycling endosome) populations in axons and dendrites in vitro and in the soma in vivo. Surprisingly, TrkA-NGF signaling endosomes in dendrites undergo dynamic trafficking events, including putative fusion and fission. Overall, we find that signaling endosomes do not remain as a singular endosomal subtype but instead exist in multiple populations that undergo dynamic endosomal trafficking events. These dynamic events might drive functional diversification of the signaling endosome.

The many disguises of the signalling endosome

“…In the work of Debaisieux and colleagues, other Rabs were also found associated to the purified retrograde carriers, suggesting that subpopulations of Rab7-and Rab5-positive organelles bearing specific small Rab GTPases may constitute alternative pathways with distinct function(s) [24]. Consistent with this hypothesis, it has been reported that the GTPase Rab11, generally associated to recycling cargoes directed to the plasma membrane, is also cotransported in TrkA-containing retrograde carriers in sympathetic neurons [139,140].…”

“…These authors showed that, both in cultured neurons and in vivo , TrkA receptors labelled at the distal axon are found in somatic organelles that were positive for a variety of endosomal markers, including Rab7, Rab11, and EEA1. At molecular level, they found that a large proportion of the retrogradely transported TrkA in dendrites was targeted to the cell surface either in the soma or dendrites, prior to being sorted to different populations of endosomes . This novel sorting mechanism may regulate the different outputs of activated receptors, leading to dendrite‐to‐nucleus signalling or local actions (e.g.…”

Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome

“…This is in line with a recent study showing that MVB transport NGF-TrkA between the nerve terminals and the cell body in sensory neurons 43 . In sympathetic neurons Rab7 and Rab11 endosomes carry TrkA 44 . We still cannot exclude the possibility that the Rab5 endosomes visualized in axons could be Rab5-to-Rab7 conversion intermediates 27 .…”

Long‐distance regressive signaling in neural development and disease

“…Upon arrival at the cell body, progressive SEs accumulate in perinuclear regions as well as dendrites (Barford et al, 2018; Sharma et al, 2010). Presumably, these locations hint at function.…”

“…Do they move retrogradely down the axon as a uniform population and then undergo maturation and molecular diversification in the cell body; or do they travel down the axon prediversified, primed to mediate distinct functions? The answer likely lies somewhere in the middle (Barford et al, 2017, 2018; Scott‐Solomon & Kuruvilla, 2018; Wu et al, 2009; N. Yamashita & Kuruvilla, 2016; M. Ye, Lehigh, & Ginty, 2018).…”