Long-Distance Control of Synapse Assembly by Target-Derived NGF

Abstract

We report a novel role for long-distance retrograde neurotrophin signaling in the establishment of synapses in the sympathetic nervous system. Target-derived NGF is both necessary and sufficient for formation of post-synaptic specializations on dendrites of sympathetic neurons. This, in turn, is prerequisite for formation of pre-synaptic specializations but not preganglionic axonal ingrowth from the spinal cord into sympathetic ganglia. We also find that NGF–TrkA signaling endosomes travel from distal axons to cell bodies and dendrites where they promote PSD clustering. Furthermore, the p75 neurotrophin receptor restricts PSD formation, suggesting an important role for antagonistic NGF–TrkA and p75 signaling pathways during retrograde control of synapse establishment. Thus, in addition to defining the appropriate number of sympathetic neurons that survive the period of developmental cell death, target-derived NGF also exerts control over the degree of connectivity between the spinal cord and sympathetic ganglia through retrograde control of synapse assembly.

Plexin-A4-dependent retrograde semaphorin 3A signalling regulates the dendritic localization of GluA2-containing AMPA receptors

“…However, several differences may exist between Sema3A and neurotrophins. For example, neurotrophins play roles in dendritic growth and synapse formation through a cascade of phosphorylation events through Trks 45 . To date, no direct interaction between Trks and AMPA receptor subunits has been proven.…”

Neep21 as an effector of the NGF-TrkA signaling endosome

“…We have a FLAG-TrkA knock-in mouse provided by the Deppmann lab that has a FLAG tag endogenously knocked-in on the extracellular domain of the TrkA receptor 5 . This allows for easy staining and visualization of the TrkA signaling endosome.…”

“…PSDs 4,5 . For transcriptional changes in the neuron, signaling is required for long periods of time with most NGF-TrkA SEs surviving for approximately 6 hours and up to 25 7 .…”

p75-NGFR and TNFR1 Interact and Cooperate During the Sympathetic Nervous System Development

“…Then, following the final target innervation, the postganglionic dendrites and preganglionic axons form functional synapses in the ganglia. This process is regulated by a retrograde signal, which has traveled inside the axon from the final target to the dendrites (Sharma et al, 2010). The stabilization of sympathetic neurons during development depends on the target-derived neurotrophic signal, identified as nerve growth factor (NGF) (Cohen, 1960).…”

“…The vertebrate nervous system takes advantage of this strategy by overproducing circuit components, such as axons, synapses and even neurons and then refining them to achieve appropriate connectivity and function (Hamburger and LeviMontalcini, 1949;reviewed in Chao, 2003;Fitzsimonds and Poo, 1998). An emergent principal in developmental neuroscience is that pro-growth and pro-refinement signaling pathways compete with one another to promote or inhibit connectivity in order to define the architecture of the nervous system (Deppmann et al, 2008;Singh et al, 2008;Sharma et al, 2010). How cross-talk between construction and destruction cues occurs to mediate nervous system wiring remains an open question.…”