The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila

Abstract

Neurons require target-derived autocrine and paracrine growth factors to maintain proper identity, innervation, homeostasis and survival. Neuronal growth factor signaling is highly dependent on membrane traffic, Neurons are highly specialized cells that depend heavily on membrane traffic for multiple facets of their unique physiology: to facilitate the rapid release and recycling of neurotransmitter-containing synaptic vesicles, to maintain their extreme and polarized morphology and compartmentalization and to sustain and regulate intracellular transport and signaling over extremely long distances. In particular, endocytic traffic is required to control the localization and activity of the signaling proteins and transmembrane receptors that govern neuronal growth and survival. To maintain appropriate innervation and activity, neurons respond to target-derived paracrine and autocrine growth factors. These growth factors bind to receptors that are internalized and trafficked along the endocytic and endosomal pathways, exerting local effects at synapses as well as long-range and long-lasting effects at neuronal cell bodies (1). The Drosophila larval neuromuscular junction (NMJ) is an excellent model for studying the cell biology of growth factor receptor signaling in neurons as it is exquisitely accessible for genetic manipulation, electrophysiology and functional analyses (2). Of particular importance, this system offers unparalleled advantages for imaging neurons in their normal developmental context, as both motor axons and NMJs are found at the surface of filleted larvae for high-resolution microscopy, and are also visible through the larval cuticle in intact, anesthetized animals (3). Over the course of larval development, the muscle area grows 100-fold, requiring synaptic activity-dependent expansion of synaptic arbors via the addition of new synaptic varicosities or boutons (4, 5; Figure 1A). This expansion requires a number of growth signaling pathways at the NMJ, including (but not limited to) www.traffic.dk 87

The BLOC-1 Subunit Pallidin Facilitates Activity-Dependent Synaptic Vesicle Recycling

“…A variety of dynamic endosomal structures are known to exist at the presynaptic terminal, where they are involved in modulating diverse aspects of synaptic growth signaling, membrane trafficking and exchange, and synaptic vesicle recycling (Wucherpfennig et al, 2003; Rodal and Littleton, 2008; Uytterhoeven et al, 2011; Saheki and De Camilli, 2012; Kononenko and Haucke, 2015; Deshpande and Rodal, 2016). Given the inability of pldn mutants to sustain the synaptic vesicle pool during high-frequency stimulation, and the associations of BLOC-1 in controlling endosomal sorting and trafficking, we considered whether endosomal dysfunction may contribute to the failure to sustain the vesicle pool in pldn mutants.…”

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

“…8C). This activation of stress signaling appears to be a common signature of neuromuscular disease (Deshpande and Rodal 2016). Based on our finding of a potential activation in stress signaling in fly models of SMA, an important question moving forward will be to understand how loss of SMN causes this stress response.…”

SMN - A chaperone for nuclear RNP social occasions?

“…Rather, SMN-dependent activation of innate immune and other types of stress signaling pathways may be more important to neuromuscular pathophysiology than previously envisioned. 147,148,149 As the storehouse of nuclear SMN protein, the Cajal body likely plays an important role in its nuclear activities. Learning more about mechanisms of SMN nuclear-cytoplasmic trafficking and its various functions within the Cajal body should help elucidate SMN's role in organismal development and SMA etiology.…”