A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop

Trotter, Justin H.; Wang, Cosmos Yuqi; Zhou, Peng; Südhof, Thomas C.

doi:10.1101/2022.05.09.491206

Cited by 7 publications

(3 citation statements)

References 63 publications

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“…Neurexins serve as presynaptic receptors for several extracellular binding partners to facilitate synapse assembly. For α-neurexins these partners include: secreted cerebellins and neuroexophilins, as well as transmembrane proteins such as neuroligins, Dystroglycan, leucine-rich repeat transmembrane proteins (LRRTM), and Calsyntenin-3 (Boucard et al, 2005; Dai et al, 2022; Hauser et al, 2022; Kim et al, 2020; Ko et al, 2009; Sugita et al, 2001; Trotter et al, 2023). Recent work in mice has demonstrated a role for α-neurexin binding partners NLGN1 and NLGN3 at the postsynapses of mouse auditory IHCs (Ramirez et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells

Jukic,

Lei,

Cebul

et al. 2024

Preprint

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Hair cells of the inner ear rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is critical for ribbon-synapse assembly in hair cells. In both mouse and zebrafish models, loss of Nrxn3 results in significantly fewer intact ribbon synapses. In zebrafish we demonstrate that a 60% loss of synapses in nrxn3 mutants dramatically reduces both presynaptic responses in hair cells and postsynaptic responses in afferent neurons. Despite a reduction in synapse function in this model, we find no deficits in the acoustic startle response, a behavior reliant on these synapses. Overall, this work demonstrates that Nrxn3 is a critical and conserved molecule required to assemble ribbon synapses. Understanding how ribbon synapses assemble is a key step towards generating novel therapies to treat forms of age-related and noise-induced hearing loss that occur due to loss of ribbon synapses.

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Section: Discussionmentioning

confidence: 99%

Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells

Jukic,

Lei,

Cebul

et al. 2024

Preprint

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“…The specific splice isoforms of Nrxns that bind Dystroglycan are expressed by CCK + /CB 1 R + INs (66), (69) . Neurexin-3 conditional knockout (targeting all Nrxn3 isoforms) and CRISPR-mediated Dag1 knockout both result in similar synaptic deficits in olfactory bulb and prefrontal cortex (70) . While a Dystroglycan knock-in mouse with reduced glycosylation that impairs Neurexin binding (Dag1 T190M ) shows normal CCK + /CB 1 R + synapse formation by immunohistochemistry, the functionality of these synapses was not assessed by electrophysiology (27) .…”

Section: Dystroglycan Is An Essential Transsynaptic Organizing Molecu...mentioning

confidence: 99%

Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy

Jahncke

Miller

Krush

et al. 2024

eLife

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Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or POMT2, which is required for Dystroglycan glycosylation, show significant impairment of CCK+/CB1R+ IN development. CCK+/CB1R+IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK+/CB1R+ IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK+/CB1R+ IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.

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“…The combinatorial expression of synaptic cell surface proteins provides different cell types with a unique identity that can be further tuned by alternative splicing. Alternative splicing of synaptic molecules can affect their protein-protein interactions and intracellular signaling (Sudhof 2017, Ovando-Zambrano, Arias-Montano et al 2019, Li, Xie et al 2020, Gomez, Traunmuller et al 2021, Trotter, Wang et al 2023. This, in turn, expands the functional repertoire of synaptic genes and adds a layer of regulatory control.…”

Section: Introductionmentioning

confidence: 99%

Modular Splicing Is Linked to Evolution in the Synapse-Specificity Molecule Kirrel3

Traenkner,

Shennib,

Johnson

et al. 2023

eNeuro

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Kirrel3 is a cell-adhesion molecule that instructs the formation of specific synapses during brain development in mouse and Kirrel3 variants may be risk factors for autism and intellectual disabilities in humans. Kirrel3 is predicted to undergo alternative splicing but brain isoforms have not been studied. Here, we present the first in-depth characterization of Kirrel3 isoform diversity in brain using targeted, long-read mRNA sequencing of mouse hippocampus. We identified 19 isoforms with predicted transmembrane and secreted forms and show that even rare isoforms generate detectable protein in the brain. We also analyzed publicly-available long-read mRNA databases from human brain tissue and found 11 Kirrel3 isoforms that, similar to mouse, encode transmembrane and secreted forms. In mice and humans, Kirrel3 diversity arises from alternative, independent use of protein-domain coding exons and alternative early translation-stop signals. Intriguingly, the alternatively spliced exons appear at branch points in the chordate phylogenetic tree, including one exon only found in humans and their closest living relatives, the great apes. Together, these results validate a simple pipeline for analyzing isoform diversity in genes with low expression and suggest that Kirrel3 function is fine-tuned by alternative splicing and may play a role in brain evolution.Significance StatementKirrel3 is an important molecule for synapse and circuit formation with gene variants that are associated with neurodevelopmental disorders, yet Kirrel3 function remains largely unknown. Here, we report new isoforms of mouse and human Kirrel3, including secreted and transmembrane forms, that suggest a diverse repertoire of Kirrel3 actions. Importantly, we identified a new Kirrel3 exon only present in humans and the other great apes with potential to play an important role in circuit formation unique to these species.

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A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop

Cited by 7 publications

References 63 publications

Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells

Presynaptic Nrxn3 is essential for ribbon-synapse assembly in hair cells

Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy

Modular Splicing Is Linked to Evolution in the Synapse-Specificity Molecule Kirrel3

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