Alternative polyadenylation (APA) plays important roles in generating transcriptome diversity under physiological and pathological conditions. However, the underlying molecular mechanisms are poorly understood. By using systematic genetic studies and genome-wide surveys of the transcriptional landscape in C. elegans, we identify an APA pathway that is required for neuron development. We show that SYDN-1, a novel nuclear protein (Van Epps et al, 2010), can antagonize SSUP-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) Carboxyl-Terminal Domain (CTD), and controls the mRNA isoform production of two neuronal genes, unc-44/Ankryrin and dlk-1/MAPKKK. Exclusion of SSUP-72 activity at a strong internal poly(A) site (PAS) in unc-44 dampens its usage and allows the production of a neuron-specific ankyrin long isoform. Conversely, at the weak internal PAS of dlk-1, SSUP-72 exclusion promotes its usage and produces short isoform to control its activity. Dysregulation of unc-44 and dlk-1 mRNA isoforms impairs neuronal development. Our results demonstrate a mechanism by which tissue-specific and gene-specific APA is achieved via regulation of select internal PASs.
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