dTACC restricts bouton addition and regulates microtubule organization at the <i>Drosophila</i> neuromuscular junction

Chou, Vivian T.; Johnson, Seth; Long, Jennifer B.; Vounatsos, Maxime; Vactor, David Van

doi:10.1002/cm.21578

Cited by 8 publications

(7 citation statements)

References 90 publications

(139 reference statements)

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“…Our discovery of a role for presynaptic LRP4 in synaptic growth (as measured by bouton number) and subsequently, cytoskeletal organization, provides a unique opportunity to associate synaptic organizers at the membrane with the cytoskeleton. Microtubule dynamics greatly influence synaptic growth in multiple systems, and in Drosophila, perturbation of microtubule regulators can result in dramatic changes in number (Chou, Johnson, Long, et al, 2020;Lepicard et al, 2014;Mosca et al, 2012;Roos et al, 2000;Ruiz-Canada et al, 2004;Shi et al, 2019). Consistent with this idea, we found, in the absence of presynaptic LRP4, an increase in looped microtubule structures, suggesting altered cytoskeletal stability.…”

Section: Lrp4 As a Cytoskeletal Regulator During Growth And Maturationsupporting

confidence: 83%

“…Microtubule dynamics greatly influence synaptic growth in multiple systems, and in Drosophila, perturbation of microtubule regulators can result in dramatic changes in bouton number (Chou, Johnson, Long, et al, 2020;Lepicard et al, 2014;Mosca et al, 2012;Roos et al, 2000;Ruiz-Canada et al, 2004;Shi et al, 2019). Consistent with this idea, we found, in the absence of presynaptic LRP4, an increase in looped microtubule structures, suggesting altered cytoskeletal stability.…”

Section: Lrp4 As a Cytoskeletal Regulator During Growth And Maturationsupporting

confidence: 82%

“…In wild-type larvae, Futsch staining reveals branches of microtubules throughout the terminal, with looped microtubule or unbundled structures occasionally present within boutons. Loops are thought to indicate microtubule stability (Nechipurenko & Broihier, 2012;Roos et al, 2000;Shi et al, 2019), which may correlate with restricted growth (Chou, Johnson, Long, et al, 2020). Conversely, unbundled, diffuse Futsch is typically associated with disorganized microtubules (Roos et al, 2000).…”

Section: Loss Of Lrp4 Perturbs Synaptic Ultrastructurementioning

confidence: 99%

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Neuronal LRP4 directs the development, maturation, and cytoskeletal organization of peripheral synapses

DePew,

Bruckner,

O’Connor-Giles

et al. 2023

Preprint

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Synapse development requires multiple signaling pathways to accomplish the myriad of steps needed to ensure a successful connection. Transmembrane receptors on the cell surface are optimally positioned to facilitate communication between the synapse and the rest of the neuron and often function as synaptic organizers to synchronize downstream signaling events. One such organizer, the LDL receptor-related protein LRP4, is a cell surface receptor most well-studied postsynaptically at mammalian neuromuscular junctions. Recent work, however, has identified emerging roles for LRP4 as a presynaptic molecule, but how LRP4 acts as a presynaptic organizer, what roles LRP4 plays in organizing presynaptic biology, and the downstream mechanisms of LRP4 are not well understood. Here we show that LRP4 functions presynaptically atDrosophilaneuromuscular synapses, acting in motor neurons to instruct multiple aspects of pre- and postsynaptic development. Loss of presynaptic LRP4 results in a range of developmental defects, impairing active zone organization, synapse growth, physiological function, microtubule organization, synaptic ultrastructure, and synapse maturation. We further demonstrate that LRP4 promotes most aspects of presynaptic development via a downstream SR-protein kinase, SRPK79D. SRPK79D overexpression suppresses synaptic defects associated with loss oflrp4. These data demonstrate a function for LRP4 as a peripheral synaptic organizer acting presynaptically, highlight a downstream mechanism conserved with its CNS function, and indicate previously unappreciated roles for LRP4 in cytoskeletal organization, synapse maturation, and active zone organization, underscoring its developmental importance.

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Section: Lrp4 As a Cytoskeletal Regulator During Growth And Maturationsupporting

confidence: 83%

Section: Lrp4 As a Cytoskeletal Regulator During Growth And Maturationsupporting

confidence: 82%

Section: Loss Of Lrp4 Perturbs Synaptic Ultrastructurementioning

confidence: 99%

See 1 more Smart Citation

Neuronal LRP4 directs the development, maturation, and cytoskeletal organization of peripheral synapses

DePew,

Bruckner,

O’Connor-Giles

et al. 2023

Preprint

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“…The transgenes were driven with ubiquitous UH1 -Gal4 or neuronal elav -Gal4. The NMJ glutamatergic synapse is used to assay disease model neurotransmission in all variants [ 26 , 27 ]. Employing TEVC recording, we compare mutants to genetic background control ( w 1118 ) and transgenic lines to driver controls ( UH1 -Gal4/ w 1118 and elav -Gal4/ w 1118 ).…”

Section: Resultsmentioning

confidence: 99%

FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission

et al. 2023

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Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients and corkscrew (csw) homolog LoF/GoF elevate glutamatergic transmission. Cell-targeted RNAi and neurotransmitter release analyses reveal a presynaptic requirement. Consistently, all mutants exhibit reduced synaptic depression during high-frequency stimulation. Both LoF and GoF mutants also show impaired synaptic plasticity, including reduced facilitation, augmentation, and post-tetanic potentiation. NS/NSML diseases are characterized by elevated MAPK/ERK signaling, and drugs suppressing this signaling restore normal neurotransmission in mutants. Fragile X syndrome (FXS) is likewise characterized by elevated MAPK/ERK signaling. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Moreover, phosphorylated ERK (pERK) is increased in dfmr1 and csw null presynaptic boutons. We find presynaptic pERK activation in response to stimulation is reduced in dfmr1 and csw nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function, showing FMRP and Csw/SHP2 act within the same signaling pathway. Thus, a FMRP and SHP2 MAPK/ERK regulative mechanism controls basal and activity-dependent neurotransmission strength.

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“…In order to maintain synaptic homeostasis, the presynaptic terminal must grow as well, continuously adding synaptic boutons (reviewed in Menon et al, 2013). The disruption of several cytoskeletal components has been found to impede the homeostatic balance between presynaptic terminal and muscle growth, resulting in both decreased and increased growth of the presynaptic terminal as measured by the number of boutons in third instar larvae (Roos et al, 2000; Sherwood et al, 2004; Pielage et al, 2006; Pawson et al, 2008; Graf et al, 2011; Zhao et al, 2013; Blunk et al, 2014; Mao et al, 2014; Migh et al, 2018; Chou et al, 2020). Many of these effects have been attributed to cytoskeletal proteins acting within the neuron, while our knowledge of postsynaptic cytoskeletal elements that contribute to synaptic growth are limited (Pielage et al, 2006; Blunk et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Dynein acts to cluster glutamate receptors and traffic the PIP5 kinase, Skittles, to regulate postsynaptic membrane organization at the neuromuscular junction

Neisch

Pengo

Avery

et al. 2021

Preprint

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Cytoplasmic dynein is essential in motoneurons for retrograde cargo transport that sustains neuronal connectivity. Little, however, is known about dynein's function on the postsynaptic side of the circuit. Here we report distinct postsynaptic roles for dynein at neuromuscular junctions (NMJs). Intriguingly, we show that dynein punctae accumulate postsynaptically at glutamatergic synaptic terminals. Moreover, Skittles, a phosphatidylinositol 4-phosphate 5-kinase that produces PI(4,5)P2 to organize the spectrin cytoskeleton, also localizes specifically to glutamatergic synaptic terminals. Depletion of postsynaptic dynein disrupts the accumulation of Skittles, PI(4,5)P2 phospholipid, and organization of the spectrin cytoskeleton at the postsynaptic membrane. Coincidental with dynein depletion, we observe an increase in the clusters size of ionotropic glutamate receptor (iGluR), and an increase in the amplitude and frequency of mEJPs. However, PI(4,5)P2 levels do not affect iGluR clustering and dynein does not affect the protein levels of iGluR subunits at the NMJ, suggesting a separate, transport independent function for dynein in iGluR cluster organization. As dynein punctae closely associate with iGluR clusters, we propose that dynein physically tethers iGluR clusters at the postsynaptic membrane to ensure proper synaptic transmission.

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dTACC restricts bouton addition and regulates microtubule organization at the Drosophila neuromuscular junction

Cited by 8 publications

References 90 publications

Neuronal LRP4 directs the development, maturation, and cytoskeletal organization of peripheral synapses

Neuronal LRP4 directs the development, maturation, and cytoskeletal organization of peripheral synapses

FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission

Dynein acts to cluster glutamate receptors and traffic the PIP5 kinase, Skittles, to regulate postsynaptic membrane organization at the neuromuscular junction

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