Journal Article

Deficiency of the splicing factor <i>Sfrs10</i> results in early embryonic lethality in mice and has no impact on full-length <i>SMN</i>/<i>Smn</i> splicing

Ylva Mende, Miriam Jakubik, Markus Riessland, Frank Schoenen, Kristina Roßbach, André Kleinridders, Christoph Köhler, Thorsten Buch and Brunhilde Wirth

in Human Molecular Genetics

Volume 19, issue 11, pages 2154-2167
Published in print June 2010 | ISSN: 0964-6906
Published online February 2010 | e-ISSN: 1460-2083 | DOI:
Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice and has no impact on full-length SMN/Smn splicing

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The SR-like splicing factor SFRS10 (Htra2-beta1) is well known to influence various alternatively spliced exons without being an essential splicing factor. We have shown earlier that SFRS10 binds SMN1/SMN2 RNA and restores full-length (FL)-SMN2 mRNA levels in vitro. As SMN1 is absent in patients with spinal muscular atrophy (SMA), the level of FL-SMN2 determines the disease severity. Correct splicing of SMN2 can be facilitated by histone deacetylase inhibitors (HDACis) via upregulation of SFRS10. As HDACis are already used in SMA clinical trials, it is crucial to identify the spectrum of alternatively spliced transcripts modulated by SFRS10, because elevated SFRS10 levels may influence or misregulate also other biological processes. To address this issue, we generated a conditional Sfrs10 allele in mice using the Cre/loxP system. The ubiquitous homozygous deletion of Sfrs10, however, resulted in early embryonic lethality around E7.5, indicating an essential role of Sfrs10 during mouse embryogenesis. Deletion of Sfrs10 with recombinant Cre in murine embryonic fibroblasts (MEFs) derived from Sfrs10fl/fl embryos increased the low levels of SmnΔ7 3–4-fold, without affecting FL-Smn levels. The weak influence of Sfrs10 on Smn splicing was further proven by a Hb9-Cre driven motor neuron-specific deletion of Sfrs10 in mice, which developed normally without revealing any SMA phenotype. To assess the role of Sfrs10 on FL-SMN2 splicing, we established MEFs from Smn−/−;SMN2tg/tg;Sfrs10fl/fl embryos. Surprisingly, deletion of Sfrs10 by recombinant Cre showed no impact on SMN2 splicing but increased SMN levels. Our findings highlight the complexity by which alternatively spliced exons are regulated in vivo.

Journal Article.  8197 words.  Illustrated.

Subjects: Genetics and Genomics

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