Our understanding of endogenous small RNA pathways has grown dramatically over the past twenty years to encompass a host of gene regulatory activities, ranging from mRNA decay and translational repression in the cytoplasm, to transcriptional modulation in the nucleus. In these pathways, Argonautes (AGOs) are guided to target transcripts by small RNA binding partners via sequence complementarity. Upon recruitment to their targets, Argonautes in turn engage other regulatory proteins to effectively execute various gene regulatory outcomes. Although many aspects of small RNA mediated gene regulation have been studied at depth, one that has yet to be explored thoroughly is the role of Argonaute/small RNA pathways in splicing. Several recent studies have implicated human Argonaute/small RNA pathways in influencing alternative splicing (Allo et al., 2014, Ameyar-Zazoua et al., 2012). Conversely, stalled spliceosomes have been shown to trigger small RNA mediated genome defense in fungi (Dumesic et al. 2013). These tantalizing initial results open the possibility that splicing and small RNA pathways could be intricately linked to provide combinatorial regulation of gene expression and/or genome defense over a broad range of species.With 26 Argonautes and four types of endogenous small RNAs, C. elegans possesses a rich tapestry of small RNA mediated gene regulatory activity. In C. elegans, thus far one report has implicated small RNA pathways (CSR-1/22G-RNA and PRG-1/piRNA) in the alternative splicing of a single transcript, tor (target of rapamycin) (Barberan-Soler et al., 2014). CSR-1 is an essential Argonaute that plays a key role in positively regulating the majority of germline transcripts at the transcriptional level (Wedeles, Wu and Claycomb, 2013; Seth et al., 2013; Conine et al., 2013; Cecere et al., 2014). Two additional studies have revealed changes in alternative splicing patterns for a number of germline genes that are also the targets of the CSR-1 small RNA pathway (Ramani et al., 2010; Ortiz et al., 2014), opening the possibility that the CSR-1 small RNA pathway could play important roles in splicing germline transcripts. A role for CSR-1 in splicing is further supported by our preliminary data, which show a physical interaction with a conserved splicing factor. Ongoing transcriptome and phenotypic analysis of various strains in which
csr-1 or the splicing factor are lost will shed led light on the impact of these factors on splicing across the genome, and may provide key insights into the role of small RNA pathways in splicing during C. elegans development. .