γ-secretase promotes Drosophila postsynaptic development through the cleavage of a Wnt receptor

Restrepo, Lucas; DePew, Alison T.; Moese, Elizabeth R.; Tymanskyj, Stephen R.; Parisi, Michael; Aimino, Michael A; Duhart, Juan Carlos; Hong, Fei; Mosca, Timothy J.

doi:10.1016/j.devcel.2022.05.006

Cited by 22 publications

(29 citation statements)

References 160 publications

(237 reference statements)

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“…DLG1 is notably expressed at the NMJ where it plays many diverse roles in postsynaptic organization, synaptic maturation, and development (Astorga et al, 2016; Budnik et al, 1996; Mendoza et al, 2003; Parnas et al, 2001; Thomas et al, 2000). DLG1 labels the region of the bouton immediately surrounding the presynaptic membrane but does not extend completely into the cytoskeletal shell surrounding the bouton (Budnik et al, 1996; Lahey et al, 1994; Pielage et al, 2006; Restrepo et al, 2022; Wang et al, 2011). Though commonly used as a postsynaptic marker, there is genetic evidence that DLG1 can also function presynaptically at the NMJ (Astorga et al, 2016; Budnik et al, 1996; Mendoza et al, 2003) though the majority of its functions are postsynaptic.…”

Section: Resultsmentioning

confidence: 99%

“…Larvae were processed for antibody staining as described (Mosca and Schwarz, 2010; Restrepo et al, 2022). Wandering third instar larvae were grown in population cages (Genesee, no.…”

Section: Methodsmentioning

confidence: 99%

“…Images were centered on the glomerulus of interest and the z-boundaries were set based on the appearance of the two synaptic labels - Brp-Short-mStraw and DLG1-V5. Images were analyzed three dimensionally using the Imaris Software 9.7.1 (Oxford Instruments, Abingdon, UK) on a custom-built image processing computer (Digital Storm, Fremont, CA) following previously established methods (Mosca and Luo, 2014; Mosca et al, 2017; Restrepo et al, 2022). Both Brp-Short and DLG1-V5 puncta were quantified using the “Spots” function with a spot size of 0.6 μm.…”

Section: Methodsmentioning

confidence: 99%

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A conditional strategy for cell-type specific labeling of endogenous excitatory synapses inDrosophilareveals subsynaptic architecture

Parisi

Aimino

Mosca

2022

Preprint

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Chemical neurotransmission occurs at specialized contacts where presynaptic neurotransmitter release machinery apposes clusters of postsynaptic neurotransmitter receptors and signaling molecules. A series of elegantly complex events underlies the recruitment of pre- and postsynaptic proteins to sites of neuronal connection and enables the correct three-dimensional synaptic organization that underlies circuit processing and computation. To better study the developmental events of synaptogenesis in individual neurons, we need cell-type specific strategies to visualize the individual proteins at their endogenous levels at synapses. Though such strategies exist for a variety of presynaptic proteins, postsynaptic proteins remain less studied due to a paucity of reagents that allow visualization of endogenous individual postsynapses in a cell-type specific manner. To study excitatory postsynapses, we engineered dlg1[4K], a conditional, epitope-tagged marker of the excitatory postsynaptic density in Drosophila. In combination with binary expression systems, dlg1[4K] effectively labels postsynaptic regions at both peripheral neuromuscular and central synapses in larvae and adults. Using dlg1[4K], we find that distinct rules govern the postsynaptic organization of different adult neuron classes, that multiple binary expression systems can concurrently label pre- and postsynaptic regions of synapses in a cell-type-specific manner, and for the first time, visualize neuronal DLG1 at the neuromuscular junction. These results validate a novel strategy for conditional postsynaptic labeling without the caveats of overexpression and demonstrate new principles of subsynaptic organization. The use of dlg1[4K] marks a notable advancement in studying cell-type specific synaptic organization in Drosophila and the first example of a general postsynaptic marker to complement existing presynaptic strategies.

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Section: Resultsmentioning

confidence: 99%

“…Larvae were processed for antibody staining as described (Mosca and Schwarz, 2010; Restrepo et al, 2022). Wandering third instar larvae were grown in population cages (Genesee, no.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A conditional strategy for cell-type specific labeling of endogenous excitatory synapses inDrosophilareveals subsynaptic architecture

Parisi

Aimino

Mosca

2022

Preprint

Self Cite

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“…S5 which were fixed for 10 minutes). For α-Fz2 staining, wandering 3 rd instar larvae were dissected in 0 mM Ca 2+ modified Drosophila saline (Restrepo et al, 2022) and fixed in 4% paraformaldehyde for 20 minutes. Washes and antibody dilutions were conducted using PBS containing 0.2% Triton X-100 (0.2% PBX), except Fz2-C stain washes and antibody dilutions which were conducted using PBS containing 0.3% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Dresselhaus

Harris

Koles

et al. 2023

Preprint

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Exosomes are membrane-bound vesicles released by many cells including neurons, carrying cargoes involved in signaling and disease. It has been unclear whether exosomes promote intercellular signaling in vivo or serve primarily to dispose of unwanted cargo. This is because manipulations of exosome cargo expression or traffic often result in their depletion from the donor cell, making it difficult to distinguish whether these cargoes act cell-autonomously or through transcellular transfer. Exosomes arise when multivesicular endosomes fuse with the plasma membrane, releasing their intralumenal vesicles outside the cell. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of exosome cargoes from Drosophila motor neurons, without depleting them from the donor presynaptic terminal. Cargoes and autophagic vacuoles accumulate in presynaptic terminals, suggesting that compensatory autophagy follows endosome dysfunction. Surprisingly, exosome cargoes Synaptotagmin-4 (Syt4) and Evenness Interrupted (Evi) retain many of their signaling activities upon ESCRT depletion, despite being trapped in presynaptic terminals. Thus, these cargoes may not require intercellular transfer, and instead are likely to function cell autonomously in the motor neuron. Our results indicate that synaptic exosome release depends on ESCRT, and serves primarily as a proteostatic mechanism for at least some cargoes.

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“…In addition, Shank assists synaptic growth and maturation through affecting the internalization of the transmembrane Wnt receptor Frizzled-2 (Fz2) [219]. It has been well studied that internalization and cleavage of Fz2 play an important role in modulating synapse development [220,221]. Among the three members, Shank2 and Shank3 contain a sterile-alpha-motif domain at their C-terminal that can bind Zn 2+ , while Shank1 is insensitive to Zn 2+ [222,223].…”

Section: Modulation and Function Of Intracellular Zn2+ Signals In Neu...mentioning

confidence: 99%

Neuronal signalling of zinc: from detection and modulation to function

et al. 2022

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Zinc is an essential trace element that stabilizes protein structures and allosterically modulates a plethora of enzymes, ion channels and neurotransmitter receptors. Labile zinc (Zn 2+ ) acts as an intracellular and intercellular signalling molecule in response to various stimuli, which is especially important in the central nervous system. Zincergic neurons, characterized by Zn 2+ deposits in synaptic vesicles and presynaptic Zn 2+ release, are found in the cortex, hippocampus, amygdala, olfactory bulb and spinal cord. To provide an overview of synaptic Zn 2+ and intracellular Zn 2+ signalling in neurons, the present paper summarizes the fluorescent sensors used to detect Zn 2+ signals, the cellular mechanisms regulating the generation and buffering of Zn 2+ signals, as well as the current perspectives on their pleiotropic effects on phosphorylation signalling, synapse formation, synaptic plasticity, as well as sensory and cognitive function.

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γ-secretase promotes Drosophila postsynaptic development through the cleavage of a Wnt receptor

Cited by 22 publications

References 160 publications

A conditional strategy for cell-type specific labeling of endogenous excitatory synapses inDrosophilareveals subsynaptic architecture

A conditional strategy for cell-type specific labeling of endogenous excitatory synapses inDrosophilareveals subsynaptic architecture

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Neuronal signalling of zinc: from detection and modulation to function

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