Nuclear pre-mRNA 3′-end processing regulates synapse and axon development in <i>C. elegans</i>

Epps, Heather Van; Dai, Ya; Qi, Yingchuan; Goncharov, Alexandr; Jin, Yishi

doi:10.1242/dev.049692

Cited by 19 publications

(22 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pfs2 inactivation in fission yeast also leads to defects in chromosome replication and segregation (Wang et al 2005). Wdr33/Pfs2 has been shown to regulate synapse and axon development in Caenorhabditis elegans (Van Epps et al 2010). Mutations in the plant Wdr33 homolog FY lead to aberrant mRNA alternative polyadenylation and defective flowering time control (Simpson et al 2003).…”

Section: Discussionmentioning

confidence: 99%

CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing

et al. 2014

View full text Add to dashboard Cite

AAUAAA is the most highly conserved motif in eukaryotic mRNA polyadenylation sites and, in mammals, is specifically recognized by the multisubunit CPSF (cleavage and polyadenylation specificity factor) complex. Despite its critical functions in mRNA 39 end formation, the molecular basis for CPSF-AAUAAA interaction remains poorly defined. The CPSF subunit CPSF160 has been implicated in AAUAAA recognition, but direct evidence has been lacking. Using in vitro and in vivo assays, we unexpectedly found that CPSF subunits CPSF30 and Wdr33 directly contact AAUAAA. Importantly, the CPSF30-RNA interaction is essential for mRNA 39 processing and is primarily mediated by its zinc fingers 2 and 3, which are specifically targeted by the influenza protein NS1A to suppress host mRNA 39 processing. Our data suggest that AAUAAA recognition in mammalian mRNA 39 processing is more complex than previously thought and involves multiple protein-RNA interactions.

show abstract

Section: Discussionmentioning

confidence: 99%

CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In a genetic screen for regulators of synapse formation, we previously identified the novel nuclear protein SYDN-1 (Van Epps et al 2010). sydn-1(0)-null mutants exhibit mild behavioral deficits but display strong genetic synergy with other mutants affecting synaptic development.…”

Section: Resultsmentioning

confidence: 99%

“…sydn-1(0)-null mutants exhibit mild behavioral deficits but display strong genetic synergy with other mutants affecting synaptic development. For example, double mutants of sydn-1(0) with syd-2(0)/ α-liprin display severe paralysis, diminished synapse number, and excessive axon branching-phenotypes not found in sydn-1(0) or syd-2(0) single mutants (Van Epps et al 2010). We took advantage of these synthetic behavioral deficits and isolated a large number of genetic suppressors (Supplemental Material).…”

Section: Resultsmentioning

confidence: 99%

“…Their roles in the nervous system are largely unknown. The novel nuclear protein SYDN-1 was previously discovered in a genetic enhancer screen for synapse formation and was subsequently shown to negatively regulate pfs-2 (Van Epps et al 2010), the ortholog of human WDR33, an obligatory subunit of the CPSF complex that binds the AAUAAA hexamer (Chan et al 2014;Schonemann et al 2014). While the genetic evidence indicates that SYDN-1 inhibits NpolyA activity, it is not known which step of NpolyA and what genes regulated by SYDN-1 are critical for neuronal development.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development

Chen

Zhou

et al. 2015

Genes Dev.

Self Cite

View full text Add to dashboard Cite

Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathway controlling APA in the Caenorhabditis elegans nervous system. Loss of function in ssup-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) C-terminal domain (CTD), dampens transcription termination at a strong intronic polyadenylation site (PAS) in unc-44/ankyrin yet promotes termination at the weak intronic PAS of the MAP kinase dlk-1. A nuclear protein, SYDN-1, which regulates neuronal development, antagonizes the function of SSUP-72 and several nuclear polyadenylation factors. This regulatory pathway allows the production of a neuron-specific isoform of unc-44 and an inhibitory isoform of dlk-1. Dysregulation of the unc-44 and dlk-1 mRNA isoforms in sydn-1 mutants impairs neuronal development. Deleting the intronic PAS of unc-44 results in increased pre-mRNA processing of neuronal ankyrin and suppresses sydn-1 mutants. These results reveal a mechanism by which regulation of CTD phosphorylation controls coding region APA in the nervous system.[Keywords: pre-mRNA 3 ′ end processing; axon and synapse development; C. elegans; SYDN-1; UNC-44/ankyrin; DLK-1/MAP kinase]

show abstract

“…A novel nuclear protein SYDN-1 inhibits SSUP-72, a Ser5 phosphatase for the C-terminal domain of RNA polymerase II. In neurons, this inhibition attenuates the use of an internal polyadenylation site (PAS) in unc-44, allowing downstream pre-mRNA polyadenylation and subsequent production of UNC-44L protein (Chen et al, 2015;Van Epps et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific regulation of alternative polyadenylation represses expression of a neuronal ankyrin isoform in C. elegans epidermal development

2017

Self Cite

View full text Add to dashboard Cite

Differential mRNA polyadenylation plays an important role in shaping the neuronal transcriptome. In C. elegans, several ankyrin isoforms are produced from the unc-44 locus through alternative polyadenylation. Here, we identify a key role for an intronic polyadenylation site (PAS) in temporal-and tissue-specific regulation of UNC-44/ankyrin isoforms. Removing an intronic PAS results in ectopic expression of the neuronal ankyrin isoform in non-neural tissues. This mis-expression underlies epidermal developmental defects in mutants of the conserved tumor suppressor death-associated protein kinase dapk-1. We have previously reported that the use of this intronic PAS depends on the nuclear polyadenylation factor SYDN-1, which inhibits the RNA polymerase II CTD phosphatase SSUP-72. Consistent with this, loss of sydn-1 blocks ectopic expression of neuronal ankyrin and suppresses epidermal morphology defects of dapk-1. These effects of sydn-1 are mediated by ssup-72 autonomously in the epidermis. We also show that a peptidyl-prolyl isomerase PINN-1 antagonizes SYDN-1 in the spatiotemporal control of neuronal ankyrin isoform. Moreover, the nuclear localization of PINN-1 is altered in dapk-1 mutants. Our data reveal that tissue and stage-specific expression of ankyrin isoforms relies on differential activity of positive and negative regulators of alternative polyadenylation.

show abstract

Nuclear pre-mRNA 3′-end processing regulates synapse and axon development in C. elegans

Cited by 19 publications

References 70 publications

CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing

CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing

Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development

Tissue-specific regulation of alternative polyadenylation represses expression of a neuronal ankyrin isoform in C. elegans epidermal development

Contact Info

Product

Resources

About