An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus

Nguyen, Thi-Minh; Schreiner, Dietmar; Xiao, Le; Bornmann, Caroline; Scheiffele, Peter

doi:10.7554/elife.22757

Cited by 68 publications

(93 citation statements)

References 54 publications

(86 reference statements)

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“…A recent paper highlighted the fact that the distinctive features of two different Schaffer-collateral projections differentially regulate mushroom spine density and high-magnitude LTP in the SO layer, organized by heterophilic type II cadherins (Basu et al, 2017). Moreover, Nrxn genes show differential, but overlapping, isoform-and region-dependent expression in different classes of neurons, and undergo highly distinctive, cell type-specific alternative splicing (Nguyen et al, 2016;Ullrich et al, 1995). One plausible scenario would be that CA3 neurons projecting to CA1 neurons in the SR layer, but not the SO layer, express higher levels of SS4-positive Nrxns at their nerve terminals.…”

Section: Discussionmentioning

confidence: 99%

Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

Kim

et al. 2020

Preprint

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Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, we show that β-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive β-Nrxn variants, but not insertnegative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuronspecific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs, and moderate impairment of light-induced anxiety-like behaviors in mice. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits. ResultsClstn3 directly binds β-Nrxns. Our previous cell surface-binding assays used a variety of Nrxn1α deletion variants derived from the bovine Nrxn1α gene or Nrxn1β variants derived from the rat Nrxn1β gene (Um et al., 2014). These vectors have long been used to characterize Nrxn interactions with neuroligins (NLs) and other ligands, including leucine-rich repeat transmembrane neuronal proteins (LRRTMs), neurexophilins, and latrophilin-1 (Boucard et al., 2012;Ko et al., 2009a;Missler et al., 1998). However, using Nrxn vectors constructed from mouse Nrxn genes, Craig and colleagues reported that Nrxn1α, but not Nrxn1β, binds to Clstn3 (Pettem et al., 2013). To resolve this discrepancy, we performed affinity chromatography of solubilized mouse synaptosomes using immobilized recombinant Ig-Clstn3 followed by mass spectrometry (MS). Intriguingly, among the captured proteins was a tryptic peptide unique to Nrxn1β (in addition to Nrxn1α peptides) ( Figures 1A-D; see Table 1). To confirm binding between Clstn3 and Nrxn1β, we engineered mouse Nrxn1β expression constructs and performed cell surface-binding assays. We found robust binding of Ig-Clstn3 to HEK293T cells expressing C-terminally FLAG-tagged mNrxn1β lacking (mNrxn1β -SS4 -FLAG) or containing (mNrxn1β +SS4 -FLAG) the SS4 insert (Figures 1E and 1F). In assays measuring dimeric ligand binding to mNrxn-expressing cell surfaces, Ig-Clstn3 interacted with both mNrxn1β -SS4 and mNrxn1β +SS4 with nanomolar affinity (Figures 1G and 1H). Kd values calculated by Scatchard analyses were 51.39 ± 5.26 nM for Nrxn1β +SS4 and 105.94 ± 7.89 nM for Nrxn1β -SS4 (Figures 1G and 1H). These findings indicate that Clstn3 binds Nrxn1β with high affinity and exhibits a slight preference for SS4 insert-positive splice variants. To investigate differences between bovine and rat Nrxn1 plasmids (bNrxn1α and rNrxn1β) used in our previous studies and t...

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Section: Discussionmentioning

confidence: 99%

Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

Kim

et al. 2020

Preprint

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“…Until recently AS had only been investigated within whole mouse brains or within heterogeneous cellular populations and investigated its role only at set stages (Dillman et al, 2013;Zhang et al, 2014). Recent work has however been able to implicate AS in neurogenesis and cell fate determination (Linares et al, 2015;Zhang et al, 2016), synaptic maintenance and plasticity (Iijima et al, 2011;Nguyen et al, 2016;and reviewed in Raj and Blencowe, 2015;Vuong et al, 2016). Our work expands upon these efforts by examining the cell type-specific consequences of AS during specific stages of cIN development.…”

Section: Discussionmentioning

confidence: 99%

Rbfox1 mediates cell-type-specific splicing in cortical interneurons

Jaglin

Wamsley

Favuzzi

et al. 2018

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Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin-and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs.Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.

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“…From some genes, like the Drosophila Down Syndrome Cell Adhesion Molecule ( Dscam1 ) and the mouse neurexins ( Nrxn ), thousands of cell surface recognition molecules are generated through alternative splicing (Schmucker et al., ; Schreiner et al., ; Sun et al., ). Importantly, these splice variants are functionally important as they encode self‐recognition and synapse specification, respectively (Aoto, Martinelli, Malenka, Tabuchi, & Südhof, ; Hattori et al., ; Matthews et al., ; Nguyen et al., ; Traunmüller, Gomez, Nguyen, & Scheiffele, ). Moreover, disruptions in alternative splicing programs have been linked to disease states resulting from neuronal network dysfunction, such as autism spectrum disorders (Parikshak et al., ; Quesnel‐Vallières et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…these splice variants are functionally important as they encode self-recognition and synapse specification, respectively (Aoto, Martinelli, Malenka, Tabuchi, & Südhof, 2013;Hattori et al, 2007;Matthews et al, 2007;Nguyen et al, 2016;Traunmüller, Gomez, Nguyen, & Scheiffele, 2016). Moreover, disruptions in alternative splicing programs have been linked to disease states resulting from neuronal network dysfunction, such as autism spectrum disorders (Parikshak et al, 2016;Quesnel-Vallières et al, 2016).…”

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confidence: 99%

“…These include Nova1/2, nElavl, Mbnl1/2, nSR100/SRRM4, Rbfox1/2, nPTBs, and members of the Signal Transduction Associated RNA binding (STAR) proteins: Sam68, Slm1, and Slm2 (Ehrmann et al, 2013;Iijima, Iijima, Witte, & Scheiffele, 2014;Iijima et al, 2011;Ince-Dunn et al, 2012;Lee, Tang, & Black, 2009;Li et al, 2014;Makeyev, Zhang, Carrasco, & Maniatis, 2007;Quesnel-Vallieres, Irimia, Cordes, & Blencowe, 2015;Raj & Blencowe, 2015;Saito et al, 2016;Traunmüller et al, 2016;Ule et al, 2003Ule et al, , 2005Vuong, Black, & Zheng, 2016;Wang et al, 2012). Slm1 and Slm2 show cell type-specific expression (Iijima et al, 2014;Nguyen et al, 2016;Stoss et al, 2004;Traunmüller, Bornmann, & Scheiffele, 2014), whereas Sam68 is ubiquitously expressed and functions not only in alternative splicing regulation but also other signalling processes (Chawla et al, 2009;Klein, Younts, Castillo, & Jordan, 2013;Sanchez-Jimenez & Sanchez-Margalet, 2013).…”

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confidence: 99%

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A Sam68‐dependent alternative splicing program shapes postsynaptic protein complexes

Witte

Schreiner

Scheiffele

2019

Eur J of Neuroscience

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Alternative splicing is one of the key mechanisms to increase the diversity of cellular transcriptomes, thereby expanding the coding capacity of the genome. This diversity is of particular importance in the nervous system with its elaborated cellular networks. Sam68, a member of the Signal Transduction Associated RNA-binding (STAR) family of RNA-binding proteins, is expressed in the developing and mature nervous system but its neuronal functions are poorly understood. Here, we perform genome-wide mapping of the Sam68-dependent alternative splicing program in mice. We find that Sam68 is required for the regulation of a set of alternative splicing events in pre-mRNAs encoding several postsynaptic scaffolding molecules that are central to the function of GABAergic and glutamatergic synapses. These components include Collybistin (Arhgef9), Gephyrin (Gphn), and Densin-180 (Lrrc7). Sam68-regulated Lrrc7 variants engage in differential protein interactions with signalling proteins, thus, highlighting a contribution of the Sam68 splicing program to shaping synaptic complexes. These findings suggest an important role for Sam68-dependent alternative splicing in the regulation of synapses in the central nervous system.

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An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus

Cited by 68 publications

References 54 publications

Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

Rbfox1 mediates cell-type-specific splicing in cortical interneurons

A Sam68‐dependent alternative splicing program shapes postsynaptic protein complexes

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