Abstract
Synapse formation and growth are tightly controlled processes. How synaptic growth is terminated after reaching proper size remains unclear. Here, we show that Leon, the Drosophila USP5 deubiquitinase, controls postsynaptic growth. In leon mutants, postsynaptic specializations of neuromuscular junctions are dramatically expanded, including the subsynaptic reticulum, the postsynaptic density, and the glutamate receptor cluster. Expansion of these postsynaptic features is caused by a disruption of ubiquitin homeostasis with accumulation of free ubiquitin chains and ubiquitinated substrates in the leon mutant. Accumulation of Ubiquilin (Ubqn), the ubiquitin receptor whose human homolog ubiquilin 2 is associated with familial amyotrophic lateral sclerosis, also contributes to defects in postsynaptic growth and ubiquitin homeostasis. Importantly, accumulations of postsynaptic proteins cause different aspects of postsynaptic overgrowth in leon mutants. Thus, the deubiquitinase Leon maintains ubiquitin homeostasis and proper Ubqn levels, preventing postsynaptic proteins from accumulation to confine postsynaptic growth.
Highlights
A synapse is a specialized structure where signals are transmitted from a neuron to another neuron or other target cells such as muscles
We examined neuromuscular junctions (NMJs) in third-instar larvae of leon2/19-2 mutants that died at mid-pupal stages and leon1/19-2 mutants that died at the late-third larval stages
At control NMJs, axonal terminals immunostained for presynaptic horseradish peroxidase (HRP) branched out extensively from initial targeting sites; synaptic boutons revealed by postsynaptic Discs large (Dlg) staining spread evenly along axonal tracks, displaying the beads-on-astring pattern (Figure 1A)
Summary
A synapse is a specialized structure where signals are transmitted from a neuron to another neuron or other target cells such as muscles. Formation of postsynapses requires coordinated formation of several specialized structures. One prominent postsynaptic feature at neuromuscular junctions (NMJs) is the extensively folded muscular membranes. In addition to membrane specializations, the postsynaptic density (PSD) is a common element whose size requires proper control. The PSD contains scaffolding proteins that recruit signaling protein complexes and neurotransmitter receptors, matching precisely the presynaptic active zones (Feng and Zhang, 2009; Sheng and Hoogenraad, 2007). Formations of postsynaptic membrane and PSD are tightly controlled and coordinated yet these processes remain elusive
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