The RNA-binding protein Musashi controls axon compartment-specific synaptic connectivity through ptp69D mRNA poly(A)-tailing

Landínez-Macías, María; Qi, Weihong; Bratus-Neuenschwander, Anna; Müller, Martin; Urwyler, Olivier

doi:10.1016/j.celrep.2021.109713

Cited by 6 publications

(6 citation statements)

References 126 publications

(132 reference statements)

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“… 125 , 126 , 127 , 128 Understanding synapse organization offers a window into deciphering the paradigms that govern nervous system assembly and how such developmental blueprints are disrupted by neurodevelopmental, neuropsychiatric, and even neurodegenerative diseases. In Drosophila , a number of techniques are aimed at studying three-dimensional synapse organization 5 , 16 , 17 , 20 , 21 , 129 , 130 but largely focus on presynaptic markers. A necessity for the thorough study of synaptogenesis involves distinguishing pre- from postsynaptic elements in a directed subset of neurons to examine connectivity and assess experimental outcomes.…”

Section: Discussionmentioning

confidence: 99%

A conditional strategy for cell-type-specific labeling of endogenous excitatory synapses in Drosophila

Parisi

Aimino

Mosca

2023

Cell Reports Methods

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Section: Discussionmentioning

confidence: 99%

A conditional strategy for cell-type-specific labeling of endogenous excitatory synapses in Drosophila

Parisi

Aimino

Mosca

2023

Cell Reports Methods

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“…This blueprint for development informs how synaptic organization is disrupted by neurodevelopmental, neuropsychiatric, and even neurodegenerative diseases. In Drosophila , a number of techniques are aimed at studying three-dimensional synapse organization (Chen et al, 2014; Duhart and Mosca, 2022; Landínez-Macías et al, 2021; Mosca and Luo, 2014; Mosca et al, 2017; Urwyler et al, 2015, 2019) but largely focus on general presynaptic active zone markers. A necessity for the thorough study of synaptogenesis involves distinguishing the pre- vs postsynaptic elements of the synapse in a directed subset of neurons to examine connectivity and assess experimental outcomes.…”

Section: Discussionmentioning

confidence: 99%

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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“…Msi specifically promotes a high number of synapses in one axon collateral of mechanosensory neurons, while in a different compartment of the same axon, Msi limits synapse number and prevents ectopic synaptogenesis. Thus, Msi has opposing, compartment-specific functions (Landínez-Macías et al, 2021 ; Figure 4C ). Moreover, Msi has an additional function in promoting the formation/growth of a specific axon collateral branch.…”

Section: The Musashi Rna Binding Protein Family As Master Regulators Of Neuronal Developmentmentioning

confidence: 99%

“…Moreover, Msi has an additional function in promoting the formation/growth of a specific axon collateral branch. Msi binds to the 3′UTR of the mRNA encoding the type IIA receptor protein tyrosine phosphatase Ptp69D and enhances its poly(A) tailing (Landínez-Macías et al, 2021 ). Our study proposes that the regulation of polyadenylation is a means to control translation of the ptp69D mRNA.…”

Section: The Musashi Rna Binding Protein Family As Master Regulators Of Neuronal Developmentmentioning

confidence: 99%

“…Our study proposes that the regulation of polyadenylation is a means to control translation of the ptp69D mRNA. In turn, precisely set levels of Ptp69D protein determine synaptic connectivity in one specific axon compartment (Landínez-Macías et al, 2021 ). The different compartment-specific functions downstream of an RBP present a concept of how a single “master” regulator can confer subcellular specificity of morphogenesis (in this case, synaptogenesis), thereby reducing the complexity required for the regulation of gene expression.…”

Section: The Musashi Rna Binding Protein Family As Master Regulators Of Neuronal Developmentmentioning

confidence: 99%

See 1 more Smart Citation

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Landínez-Macías

Urwyler

2021

Front. Mol. Neurosci.

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Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

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The RNA-binding protein Musashi controls axon compartment-specific synaptic connectivity through ptp69D mRNA poly(A)-tailing

Cited by 6 publications

References 126 publications

A conditional strategy for cell-type-specific labeling of endogenous excitatory synapses in Drosophila

A conditional strategy for cell-type-specific labeling of endogenous excitatory synapses in Drosophila

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

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

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