PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

Zheng, Sika; Gray, Erin E.; Chawla, Geetanjali; Porse, Bo T.; O’Dell, Thomas J.; Black, Douglas L.

doi:10.1038/nn.3026

Cited by 212 publications

(269 citation statements)

References 49 publications

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“…However, during early development it is spliced to include a 3UI and the mRNA is degraded. Psd-95 protein is not detected until later in development, when the splicing pattern shifts in favor of the non 3UI-containing form [76].…”

Section: A a Bicknell Et Almentioning

confidence: 93%

Introns in UTRs: Why we should stop ignoring them

et al. 2012

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Although introns in 5 0 -and 3 0 -untranslated regions (UTRs) are found in many protein coding genes, rarely are they considered distinctive entities with specific functions. Indeed, mammalian transcripts with 3 0 -UTR introns are often assumed nonfunctional because they are subject to elimination by nonsense-mediated decay (NMD). Nonetheless, recent findings indicate that 5 0 -and 3 0 -UTR intron status is of significant functional consequence for the regulation of mammalian genes. Therefore these features should be ignored no longer.

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Section: A a Bicknell Et Almentioning

confidence: 93%

Introns in UTRs: Why we should stop ignoring them

et al. 2012

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“…Detailed studies of splicing repression by PTBP1 have examined several exons including the N1-exon of the Src pre-mRNA, exon 9 of GABA A receptor-γ2 subunit, and exon SM of α-actinin (Ashiya and Grabowski 1997;Chan and Black 1997;Southby et al 1999). The PTBP2 target exons overlap with those of PTBP1, but are not identical (Markovtsov et al 2000;Boutz et al 2007;Spellman et al 2007;Llorian et al 2010;Tang et al 2011;Zheng et al 2012;Linares et al 2015), and the two proteins show differential targeting of the Src N1 exon, CACNA1C exon 8, and other exons (Chan and Black 1997;Modafferi and Black 1999;Amir-Ahmady et al 2005). The mechanistic basis for this difference in activity is not known.…”

Section: Introductionmentioning

confidence: 99%

“…PTBP2 is expressed in neurons, testis, and certain other cells. PTBP1 is expressed in neuronal progenitor cells but is replaced by PTBP2 during early neuronal differentiation (Polydorides et al 2000;Boutz et al 2007;Makeyev et al 2007;Licatalosi et al 2012;Zheng et al 2012;Gueroussov et al 2015;Linares et al 2015). The switch from PTBP1 to PTBP2 alters the splicing of exons that are more sensitive to PTBP1, thus reprogramming neuronal splicing.…”

Section: Introductionmentioning

confidence: 99%

“…The expression of PTBP2 is later reduced, leading to a second switch in the splicing program as neurons mature. The changes in the levels of these two regulators lead to changes in the expression and structure of many proteins playing critical roles in neuronal differentiation and maturation (Licatalosi et al 2012;Zheng et al 2012;Xue et al 2013;Li et al 2014;Linares et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Multiple determinants of splicing repression activity in the polypyrimidine tract binding proteins, PTBP1 and PTBP2

Keppetipola

Yeom

Hernandez

et al. 2016

RNA

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Most human genes generate multiple protein isoforms through alternative pre-mRNA splicing, but the mechanisms controlling alternative splicing choices by RNA binding proteins are not well understood. These proteins can have multiple paralogs expressed in different cell types and exhibiting different splicing activities on target exons. We examined the paralogous polypyrimidine tract binding proteins PTBP1 and PTBP2 to understand how PTBP1 can exhibit greater splicing repression activity on certain exons. Using both an in vivo coexpression assay and an in vitro splicing assay, we show that PTBP1 is more repressive than PTBP2 per unit protein on a target exon. Constructing chimeras of PTBP1 and 2 to determine amino acid features that contribute to their differential activity, we find that multiple segments of PTBP1 increase the repressive activity of PTBP2. Notably, when either RRM1 of PTBP2 or the linker peptide separating RRM2 and RRM3 are replaced with the equivalent PTBP1 sequences, the resulting chimeras are highly active for splicing repression. These segments are distinct from the known region of interaction for the PTBP1 cofactors Raver1 and Matrin3 in RRM2. We find that RRM2 of PTBP1 also increases the repression activity of an otherwise PTBP2 sequence, and that this is potentially explained by stronger binding by Raver1. These results indicate that multiple features over the length of the two proteins affect their ability to repress an exon.

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“…The PTC-containing PTBP1 mRNAs are then rapidly degraded in the cytoplasm by the nonsensemediated decay (NMD) machinery (Isken and Maquat 2008;Nicholson and Muhlemann 2010). Using a similar NMD mechanism, Ptbp1 represses the expression of its neuronal paralog (Ptbp2) and at least two other nervous system-specific genes (Gabbr1 and Dlg4) (Boutz et al 2007;Makeyev et al 2007;Spellman et al 2007;Zheng et al 2012). Thus, in addition to generating distinct protein isoforms, alternative splicing may cooperate with the cytoplasmic RNA surveillance machinery to control gene expression levels (Lareau et al 2007;Isken and Maquat 2008;Barash et al 2010).…”

mentioning

confidence: 99%

Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention

Yap¹,

Lim²,

Khandelia³

et al. 2012

Genes Dev.

263

295

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Differentiated cells acquire unique structural and functional traits through coordinated expression of lineagespecific genes. An extensive battery of genes encoding components of the synaptic transmission machinery and specialized cytoskeletal proteins is activated during neurogenesis, but the underlying regulation is not well understood. Here we show that genes encoding critical presynaptic proteins are transcribed at a detectable level in both neurons and nonneuronal cells. However, in nonneuronal cells, the splicing of 39-terminal introns within these genes is repressed by the polypyrimidine tract-binding protein (Ptbp1). This inhibits the export of incompletely spliced mRNAs to the cytoplasm and triggers their nuclear degradation. Clearance of these introncontaining transcripts occurs independently of the nonsense-mediated decay (NMD) pathway but requires components of the nuclear RNA surveillance machinery, including the nuclear pore-associated protein Tpr and the exosome complex. When Ptbp1 expression decreases during neuronal differentiation, the regulated introns are spliced out, thus allowing the accumulation of translation-competent mRNAs in the cytoplasm. We propose that this mechanism counters ectopic and precocious expression of functionally linked neuron-specific genes and ensures their coherent activation in the appropriate developmental context.

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PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

Cited by 212 publications

References 49 publications

Introns in UTRs: Why we should stop ignoring them

Introns in UTRs: Why we should stop ignoring them

Multiple determinants of splicing repression activity in the polypyrimidine tract binding proteins, PTBP1 and PTBP2

Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention

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