Targeted Combinatorial Alternative Splicing Generates Brain Region-Specific Repertoires of Neurexins

Abstract

Molecular diversity of surface receptors has been hypothesized to provide a mechanism for selective synaptic connectivity. Neurexins are highly diversified receptors that drive the morphological and functional differentiation of synapses. Using a single cDNA sequencing approach, we detected 1,364 unique neurexin-α and 37 neurexin-β mRNAs produced by alternative splicing of neurexin pre-mRNAs. This molecular diversity results from near-exhaustive combinatorial use of alternative splice insertions in Nrxn1α and Nrxn2α. By contrast, Nrxn3α exhibits several highly stereotyped exon selections that incorporate novel elements for posttranscriptional regulation of a subset of transcripts. Complexity of Nrxn1α repertoires correlates with the cellular complexity of neuronal tissues, and a specific subset of isoforms is enriched in a purified cell type. Our analysis defines the molecular diversity of a critical synaptic receptor and provides evidence that neurexin diversity is linked to cellular diversity in the nervous system.

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

“…Furthermore, we show that SSA-mediated deregulation of RNA splicing impairs hippocampal LTP and hippocampus-dependent memory function in mice. To the best of our knowledge, such an effect has never been demonstrated before, but is in line with targeted approaches showing, for example, that splicing of neuronal surface receptors such as neurexins is linked to synaptic function (72). Most importantly, administration of SAHA could only partially rescue SSA-mediated impairment of hippocampal LTP and memory formation.…”

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

“…The extracellular domains of α-neurexins contain six LNS (laminin-neurexin-sex hormone-binding globulin) and three EGF (epidermal growth factorlike) domains, whereas the extracellular sequence of β-neurexins only includes the last LNS6 domain of α-neurexins (5-7). Neurexin transcripts are subject to extensive alternative splicing at six conserved sites [splice site (SS)1 to SS6] to generate >1,000 unique transcripts (8)(9)(10), creating a molecular diversity that may contribute to synaptic diversity. For example, alternative splicing at SS4 regulates the affinity of LNS6 for neuroligins (11), leucine-rich repeat transmembrane neuronal proteins (LRRTMs) (12), and cerebellin-1/glutamate receptor delta-2 (GluRδ2) (13), and influences synaptic properties in vivo (14).…”

Microfluidic isoform sequencing shows widespread splicing coordination in the human transcriptome

“…S3A; Supplemental Table S2) and 110 genes using the SLR-RNA-seq data (Methods; Supplemental Table S3). The neurexin genes with mostly independent alternative exon pairs (Schreiner et al 2014;Treutlein et al 2014) serve as a negative control: Indeed, despite testing 24 alternative exon pairs for dependence, none of these neurexin exon pairs was found to be coordinated. Removing spISO-seq barcodes with <1000 short reads (which contain falsepositive molecule identifications), exon pairs of seven (PPFIBP1, KIAA1217, RECK, PPA2, PPFIA2, TPM1, and CCDC25) of the 125 genes showed increased corrected P-values (from <0.05 to 0.05-0.16).…”

“…Nonrandom combination patterns of an internal exon and a 3 ′ exon were observed in the tropomyosin 1 gene (TPM1) (Helfman et al 1986), and nonrandom combinations of alternative exons have been described in the fibronectin gene (Fededa et al 2005). Recent targeted work has established the connectivity of alternative exons in four Drosophila genes (Bolisetty et al 2015), mouse Fn1, and Drosophila Dscam (Roy et al 2015) as well as mammalian neurexins (Schreiner et al 2014;Treutlein et al 2014). In neurexins, distant alternative exons were mostly independent.…”