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New Brain Study Reveals Higher Molecular Diversity from Alternative Splicing

Thursday, October 9, 2014

A new paper from scientists in Switzerland and the US adds to recent findings about diversity of neuronal transcripts in the mammalian brain. The authors report that this study was only possible using long reads from Single Molecule, Real-Time (SMRT®) Sequencing.

Targeted Combinatorial Alternative Splicing Generates Brain Region-Specific Repertoires of Neurexins,” from lead author Dietmar Schreiner, senior author Peter Scheiffele, and collaborators, was published this month in the journal Neuron. The researchers are from the University of Basel, ETH Zurich, and North Carolina State University. This is the second study on neurexin mRNA diversity using PacBio® sequencing.

The team tackled alternative splicing in neurexins, a gene family serving as receptors with an important role in synaptic morphology and function. Neurexins are well known for their frequent use of alternative splicing to increase diversity; splicing has been shown to have an effect on molecular interactions and protein interfaces, with downstream impact on synaptic plasticity and more. This study aimed to go beyond accepted effects of alternative splicing in protein function to molecular diversity and how this splicing may “regulate temporal and spatial expression of certain neurexin isoforms,” the authors note.

Schreiner et al. used SMRT Sequencing of cDNA generated from RNA found in the brain of an adult mouse. Sequencing covered some 370,000 full-length Nrxnα transcripts. “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,” the scientists write. “This molecular diversity results from near-exhaustive combinatorial use of alternative splice insertions in Nrxn1α and Nrxn2α.”

In addition to studying the many splicing events found in these neurexin genes and working to ensure that their analysis covered even the relatively rare transcripts, the team followed up with a comparison of neurexin activity in other areas of the brain. “Notably, the relative isoform distributions and overall complexity of the Nrxn1α repertoires were significantly different in the cerebellum as compared to the cortex or whole brain,” they report. “Thus, this simpler brain structure that is composed of fewer neuronal cell types, exhibits a less varied repertoire of neurexins.”

Using PacBio sequencing to cover full transcripts allowed the scientists to find far more isoforms than was previously possible and provided a unique view of brain biology. “Our single molecule deep sequencing approach identifies novel alternative splice variants and highly combinatorial alternative exon use, but also specific stereotyped restrictions in alternative exon combinations,” they write. “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.”

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