Lark Is the Splicing Factor RBM4 and Exhibits Unique Subnuclear Localization Properties

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Abstract
Lark is an RNA-binding protein of the RNA recognition motif (RRM) class and, in Drosophila, Lark is required for embryonic development. In attempting to determine the function of human Lark we uncovered a frame-shift error in the published sequence to reveal that Lark is, in fact, RBM4, a recently described splicing regulator. We then went on to show that RBM4 localizes in nuclear speckles and nucleoli, supporting its potential role in splicing or RNA processing. Immunofluorescence imaging of full-length and mutated RBM4 revealed that the C-terminus of RBM4 is crucial for targeting to speckles. Unlike many other splicing factors, however, RBM4 does not contain an RS-domain or any other known targeting site. RBM4 redistributed to perinucleolar clusters upon the addition of a transcription inhibitor, whereas other splicing factors display increased localization to speckles in the absence of transcription. This finding is consistent with the potential existence of a novel subnuclear targeting pathway. In conclusion, RBM4 and Lark are the same protein, are localized in speckles and nucleoli, but can redistribute to perinucleolar clusters, consistent with a novel subnuclear pathway.