Key result
Drosophila muscleblind genes encode proteins with two tandem zinc finger motifs, highly similar to vertebrate MBNL proteins, and different isoforms have overlapping but divergent functions in rescuing splicing defects in vivo.
Drosophila muscleblind encodes proteins with two tandem zinc finger motifs, similar to vertebrate MBNL proteins, which regulate alternative splicing of both muscle-specific and non-muscle targets.
Should not yet alter management of splicing disorders; extends MBNL conservation evidence to Drosophila models.
Muscleblind-like proteins, Muscleblind (Mbl) in Drosophila and MBNL1-3 in vertebrates, are regulators of alternative splicing. Human MBNL1 is a key factor in the etiology of myotonic dystrophy (DM), a muscle wasting disease caused by the occurrence of toxic RNA molecules containing CUG/CCUG repeats. MBNL1 binds to these RNAs and is sequestered in nuclear foci preventing it from exerting its normal function, which ultimately leads to mis-spliced mRNAs, a major cause of the disease. Muscleblind-proteins bind to RNAs via N-terminal zinc fingers of the Cys(3)-His type. These zinc fingers are arranged in one (invertebrates) or two (vertebrates) tandem zinc finger (TZF) motifs with both fingers targeting GC steps in the RNA molecule. Here I show that mbl genes in Drosophila and in other insects also encode proteins with two TZF motifs, highly similar to vertebrate MBNL proteins. In Drosophila the different protein isoforms have overlapping but possibly divergent functions in vivo, evident by their unequal capacities to rescue the splicing defects observed in mbl mutant embryos. In addition, using whole transcriptome analysis, I identified several new splicing targets for Mbl in Drosophila embryos. Two of these novel targets, kkv (krotzkopf-verkehrt, coding for Chitin Synthase 1) and cora (coracle, coding for the Drosophila homolog of Protein 4.1), are not muscle-specific but expressed mainly in epidermal cells, indicating a function for mbl not only in muscles and the nervous system.
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Uwe Irion (2012) studied mbl mutation. mbl transgenes (one or two TZF motifs) vs. mbl mutant embryos was evaluated on Rescue of alternative splicing defects in mbl mutant embryos. Drosophila muscleblind genes encode proteins with two tandem zinc finger motifs, highly similar to vertebrate MBNL proteins, and different isoforms have overlapping but divergent functions in rescuing splicing defects in vivo.
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