Toggle Main Menu Toggle Search

ePrints

The Tissue-Specific RNA Binding Protein T-STAR Controls Regional Splicing Patterns of Neurexin Pre-mRNAs in the Brain

Lookup NU author(s): Dr Ingrid Ehrmann, Caroline Dalgliesh, Dr Marina Danilenko, Moira Crosier, Lynne Overman, Professor Helen Arthur, Professor Susan Lindsay, Dr Gavin Clowry, Dr Julian Venables, Professor David Elliott

Downloads


Abstract

The RNA binding protein T-STAR was created following a gene triplication 520–610 million years ago, which also produced its two parologs Sam68 and SLM-1. Here we have created a T-STAR null mouse to identify the endogenous functions of this RNA binding protein. Mice null for T-STAR developed normally and were fertile, surprisingly, given the high expression of T-STAR in the testis and the brain, and the known infertility and pleiotropic defects of Sam68 null mice. Using a transcriptome-wide search for splicing targets in the adult brain, we identified T-STAR protein as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of the Stxbp5l gene. T-STAR protein was most highly concentrated in forebrain-derived structures like the hippocampus, which also showed maximal Neurexin1-3 AS4 splicing repression. In the absence of endogenous T-STAR protein, Nrxn1-3 AS4 splicing repression dramatically decreased, despite physiological co-expression of Sam68. In transfected cells Neurexin3 AS4 alternative splicing was regulated by either T-STAR or Sam68 proteins. In contrast, Neurexin2 AS4 splicing was only regulated by T-STAR, through a UWAA-rich response element immediately downstream of the regulated exon conserved since the radiation of bony vertebrates. The AS4 exons in the Nrxn1 and Nrxn3 genes were also associated with distinct patterns of conserved UWAA repeats. Consistent with an ancient mechanism of splicing control, human T-STAR protein was able to repress splicing inclusion of the zebrafish Nrxn3 AS4 exon. Although Neurexin1-3 and Stxbp5l encode critical synaptic proteins, T-STAR null mice had no detectable spatial memory deficits, despite an almost complete absence of AS4 splicing repression in the hippocampus. Our work identifies T-STAR as an ancient and potent tissue-specific splicing regulator that uses a concentration-dependent mechanism to co-ordinately regulate regional splicing patterns of the Neurexin1-3 AS4 exons in the mouse brain.


Publication metadata

Author(s): Ehrmann I, Dalgliesh C, Liu Y, Danilenko M, Crosier M, Overman L, Arthur HM, Lindsay S, Clowry GJ, Venables JP, Fort P, Elliott DJ

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2013

Volume: 9

Issue: 4

Print publication date: 25/04/2013

ISSN (print): 1553-7390

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pgen.1003474

DOI: 10.1371/journal.pgen.1003474

Notes: Article no. e1003474 is 21 pp.


Altmetrics

Altmetrics provided by Altmetric


Actions

    Link to this publication


Share