Alternative titles; symbols
HGNC Approved Gene Symbol: CELF3
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:151,700,058-151,716,803 (from NCBI)
Members of the CELF family, such as CELF3, play various roles in cotranscriptional and posttranscriptional RNA processing. All CELF proteins appear to affect pre-mRNA splicing, but individual CELFs have divergent roles in regulating mRNA stability and translation (summary by Wagnon et al., 2012).
By searching databases for human sequences similar to Xenopus Brunol1, Good et al. (2000) identified a partial sequence for TNRC4, which they called BRUNOL1. The partial human protein shares 91% amino acid identity with Xenopus Brunol1.
By searching EST databases for sequences similar to CUGBP (601074), followed by PCR of a human brain cDNA library, Ladd et al. (2001) cloned TNRC4, which they called CELF3. The deduced 462-amino acid protein contains 2 N-terminal RNA recognition motifs (RRMs), a C-terminal RRM, several potential phosphorylation sites, and a nuclear localization signal near the C terminus. Ladd et al. (2001) also identified a region of allelic variation in CELF3 in which a variable number of CAG repeats encode a stretch of glutamines of unfixed length. RNA dot blot analysis detected CELF3 expression only in brain.
Using RNA dot blot analysis, Ladd et al. (2004) found that CELF3 was highly expressed in several adult brain regions, in pituitary, and in fetal brain.
By Western blot analysis of adult human cortex, Chapple et al. (2007) showed that the full-length 465-amino acid TNRC4 protein had an apparent molecular mass of about 50 kD. Epitope-tagged TNRC4 was expressed in the nucleus and cytoplasm of transfected Chinese hamster ovary cells. Removal of RRM3 led to exclusion of TNRC4 from the nucleus, confirming the presence of a C-terminal nuclear localization signal.
Ladd et al. (2001) showed that all human CELF proteins, including CELF3, bound RNA containing muscle-specific splicing enhancer (MSE) elements and could activate MSE-dependent exon inclusion of cardiac troponin T (TNNT2; 191045) minigenes in transfected quail fibroblasts.
By RT-PCR analysis of transfected Chinese hamster ovary cells, Chapple et al. (2007) showed that TNRC4 activated inclusion of exon 10 in a tau (MAPT; 157140) minigene. Deletion and mutation analyses showed that the activity of TNRC4 on tau exon 10 splicing required RRM2 in TNRC4 and an intronic element in tau pre-mRNA. The polyglutamine sequence of TNRC4 had no effect on tau exon 10 splicing. Tnrc4 -/- mice exhibited decreased inclusion of exon 10 in tau mRNA.
By genomic sequence analysis, Good et al. (2000) mapped the TNRC4 gene to chromosome 1q21.
Chapple, J. P., Anthony, K., Martin, T. R., Dev, A., Cooper, T. A., Gallo, J.-M. Expression, localization and tau exon 10 splicing activity of the brain RNA-binding protein TNRC4. Hum. Molec. Genet. 16: 2760-2769, 2007. [PubMed: 17725984] [Full Text: https://doi.org/10.1093/hmg/ddm233]
Good, P. J., Chen, Q., Warner, S. J., Herring, D. C. A family of human RNA-binding proteins related to the Drosophila Bruno transcriptional regulator. J. Biol. Chem. 275: 28583-28592, 2000. [PubMed: 10893231] [Full Text: https://doi.org/10.1074/jbc.M003083200]
Ladd, A. N., Charlet-B, N., Cooper, T. A. The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Molec. Cell. Biol. 21: 1285-1296, 2001. [PubMed: 11158314] [Full Text: https://doi.org/10.1128/MCB.21.4.1285-1296.2001]
Ladd, A. N., Nguyen, N. H., Malhotra, K., Cooper, T. A. CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific splicing enhancer-dependent alternative splicing. J. Biol. Chem. 279: 17756-17764, 2004. [PubMed: 14761971] [Full Text: https://doi.org/10.1074/jbc.M310687200]
Wagnon, J. L., Briese, M., Sun, W., Mahaffey, C. L., Curk, T., Rot, G., Ule, J., Frankel, W. N. CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function. PLoS Genet. 8: e1003067, 2012. Note: Electronic Article. [PubMed: 23209433] [Full Text: https://doi.org/10.1371/journal.pgen.1003067]