Universität zu Köln

Grellscheid, Sushma, Dalgliesh, Caroline, Storbeck, Markus, Best, Andrew, Liu, Yilei, Jakubik, Miriam, Mende, Ylva, Ehrmann, Ingrid, Curk, Tomaz ORCID: 0000-0003-4888-7256, Rossbach, Kristina, Bourgeois, Cyril F., Stevenin, James, Grellscheid, David, Jackson, Michael S., Wirth, Brunhilde ORCID: 0000-0003-4051-5191 and Elliott, David J. (2011). Identification of Evolutionarily Conserved Exons as Regulated Targets for the Splicing Activator Tra2 beta in Development. PLoS Genet., 7 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

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Abstract

Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2 beta (Sfrs10) is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2 beta is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2 beta binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl); Nestin-Cre(tg/+)). This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2 beta regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2 beta binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2 beta protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2 beta. Versions of Tra2 beta lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2 beta protein.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Grellscheid, Sushma UNSPECIFIED UNSPECIFIED UNSPECIFIED Dalgliesh, Caroline UNSPECIFIED UNSPECIFIED UNSPECIFIED Storbeck, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Best, Andrew UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Yilei UNSPECIFIED UNSPECIFIED UNSPECIFIED Jakubik, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Mende, Ylva UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehrmann, Ingrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Curk, Tomaz UNSPECIFIED orcid.org/0000-0003-4888-7256 UNSPECIFIED Rossbach, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bourgeois, Cyril F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stevenin, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Grellscheid, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Jackson, Michael S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED Elliott, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-484957
DOI:	10.1371/journal.pgen.1002390
Journal or Publication Title:	PLoS Genet.
Volume:	7
Number:	12
Date:	2011
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7404
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SEX DETERMINATION GENE; RNA-BINDING PROTEIN; MOTOR-NEURON SMN; GERM-CELLS; EXPRESSION; INCLUSION; ENHANCER; TRANSFORMER-2; GENERATION; SEQUENCE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48495