Negative feedback regulation among SR splicing factors encoded by Rbp1 and Rbp1-like in Drosophila

SR proteins constitute a widely conserved family of splicing regulators. Negative autoregulation of SR proteins has been proposed to exert homeostatic control on the splicing environment, but few examples have been studied and the role of isoforms that lack the RS domain is unclear. We show that genes Rbp1 and Rbp1-like, which encode Drosophila homologs of mammalian SRp20, negatively autoregulate and crossregulate at the level of alternative 30 splice site selection. This adjusts the relative expression of isoforms with either an RS domain or unrelated C-terminal domains (ALT) that are rich in serine and threonine. The effects of RBP1-ALT on splicing of doublesex and Rbp1-like are opposite to those of RBP1-RS and RBP1L-RS. RBP1-ALT and -RS exert opposing negative feedback on the ALT/RS ratio. However, RBP1-ALT inhibits the expression of RBP1-RS while stimulating that of RBP1L-RS. This asymmetry may contribute to changes in the RBP1-RS/RBP1L-RS ratio that are observed during development. These results provide the first example of a feedback-regulated SR protein network with evidence of an active homeostatic role for alternative isoforms.