The U1 small nuclear (sn)RNA (U1) is a multifunctional ncRNA, known for its pivotal role in pre-mRNA splicing and regulation of RNA 3′ end processing events. We recently demonstrated that a new class of human U1-like snRNAs, the variant (v)U1 snRNAs (vU1s), also participate in pre-mRNA processing events. In this study, we show that several human vU1 genes are specifically upregulated in stem cells and participate in the regulation of cell fate decisions. Significantly, ectopic expression of vU1 genes in human skin fibroblasts leads to increases in levels of key pluripotent stem cell mRNA markers, including NANOG and SOX2. These results reveal an important role for vU1s in the control of key regulatory networks orchestrating the transitions between stem cell maintenance and differentiation. Moreover, vU1 expression varies inversely with U1 expression during differentiation and cell re-programming and this pattern of expression is specifically de-regulated in iPSC-derived motor neurons from Spinal Muscular Atrophy (SMA) type 1 patient's. Accordingly, we suggest that an imbalance in the vU1/U1 ratio, rather than an overall reduction in Uridyl-rich (U)-snRNAs, may contribute to the specific neuromuscular disease phenotype associated with SMA.

Much evidence is now accumulating that, in addition to their general role in splicing, the components of the core splicing machinery have extensive regulatory potential. In particular, recent evidence has demonstrated that de-regulation of these factors cause the highest extent of alternative splicing changes compared to de-regulation of the classical splicing regulators. This lack of a general inhibition of splicing resonates the differential splicing effects observed in different disease pathologies associated with specific mutations targeting core spliceosomal components. In this review we will summarize what is currently known regarding the involvement of core spliceosomal U-snRNP complexes in perturbed tissue development and human diseases and argue for the existence of a compensatory mechanism enabling cells to cope with drastic perturbations in core splicing components. This system maintains the correct balance of spliceosomal snRNPs through differential expression of variant (v)U-snRNPs.