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

Dimitri Traenkner1, Omar Shennib1, Alyssa Johnson1

  • 1Department of Neurobiology, University of Utah, School of Medicine, Salt Lake City, UT 84112.

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|November 17, 2023
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Summary
This summary is machine-generated.

Researchers explored Kirrel3 gene variants in brain development. They discovered diverse Kirrel3 protein forms in mice and humans, suggesting a role in brain evolution and potential links to neurodevelopmental disorders.

Keywords:
Kirrel3alternative splicingcell adhesionevolutionsynapse

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Kirrel3 is a cell-adhesion molecule crucial for synapse formation during brain development.
  • Kirrel3 variants are implicated as risk factors for human autism and intellectual disabilities.
  • Previous studies predicted alternative splicing of Kirrel3, but brain-specific isoforms remained uncharacterized.

Purpose of the Study:

  • To comprehensively characterize Kirrel3 isoform diversity in the mammalian brain.
  • To investigate the generation mechanisms and evolutionary origins of Kirrel3 isoforms.
  • To establish a pipeline for analyzing isoform diversity in low-expression genes.

Main Methods:

  • Targeted, long-read mRNA sequencing of mouse hippocampus.
  • Analysis of publicly available long-read mRNA databases from human brain tissue.
  • Bioinformatic analysis to identify and compare Kirrel3 isoforms across species.

Main Results:

  • Identified 19 distinct Kirrel3 isoforms in the mouse brain, including transmembrane and secreted forms.
  • Detected 11 Kirrel3 isoforms in human brain tissue, also with transmembrane and secreted variants.
  • Found that isoform diversity is generated by alternative exon usage and alternative translation-stop signals.
  • Observed alternatively spliced exons at key evolutionary branch points, with one exon unique to humans and great apes.

Conclusions:

  • Kirrel3 function is finely tuned by alternative splicing in both mouse and human brains.
  • The diversity of Kirrel3 isoforms suggests a role in brain evolution.
  • The identified pipeline is effective for studying isoform diversity in genes with low expression.