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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/ lox P 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  Sfrs10   fl/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  −/− ; SMN2   tg/tg  ; Sfrs10   fl/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 .

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