XB-ART-49433
Development
2014 Oct 01;14119:3740-51. doi: 10.1242/dev.106658.
Show Gene links
Show Anatomy links
The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling.
???displayArticle.abstract???
Alternative splicing of pre-mRNAs is an important means of regulating developmental processes, yet the molecular mechanisms governing alternative splicing in embryonic contexts are just beginning to emerge. Polyglutamine-binding protein 1 (PQBP1) is an RNA-splicing factor that, when mutated, in humans causes Renpenning syndrome, an X-linked intellectual disability disease characterized by severe cognitive impairment, but also by physical defects that suggest PQBP1 has broader functions in embryonic development. Here, we reveal essential roles for PQBP1 and a binding partner, WBP11, in early development of Xenopus embryos. Both genes are expressed in the nascent mesoderm and neurectoderm, and morpholino knockdown of either causes defects in differentiation and morphogenesis of the mesoderm and neural plate. At the molecular level, knockdown of PQBP1 in Xenopus animal cap explants inhibits target gene induction by FGF but not by BMP, Nodal or Wnt ligands, and knockdown of either PQBP1 or WBP11 in embryos inhibits expression of fgf4 and FGF4-responsive cdx4 genes. Furthermore, PQBP1 knockdown changes the alternative splicing of FGF receptor-2 (FGFR2) transcripts, altering the incorporation of cassette exons that generate receptor variants (FGFR2 IIIb or IIIc) with different ligand specificities. Our findings may inform studies into the mechanisms underlying Renpenning syndrome.
???displayArticle.pubmedLink??? 25209246
???displayArticle.pmcLink??? PMC4197583
???displayArticle.link??? Development
???displayArticle.grants??? [+]
R01HD032429 NICHD NIH HHS , R03HD064908 NICHD NIH HHS , R01 HD032429 NICHD NIH HHS , R03 HD064908 NICHD NIH HHS
Species referenced: Xenopus laevis
Genes referenced: bmp4 cdx4 chrd fgf4 fgf8 fgfr2 gsc mapk1 myc ncam1 nodal nodal1 nodal2 nog odc1 pqbp1 sia1 snai2 sox2 szl tbxt tubb2b vegt wbp11 wnt8a
GO keywords: neural plate development [+]
???displayArticle.antibodies??? Mapk1 Ab7 Mapk Ab5 Tubb2b Ab5
???displayArticle.morpholinos??? pqbp1 MO1 pqbp1 MO2 pqbp1 MO3 pqbp1 MO4 wbp11 MO1
???displayArticle.disOnts??? Renpenning syndrome
???displayArticle.omims??? RENPENNING SYNDROME 1; RENS1
Phenotypes: Xla Wt + bmp4 + animal cap explant(Fig.6.A) [+]
Xla Wt + fgf4 + animal cap explant(Fig.6.B,C)
Xla Wt + nodal2 + animal cap explant(Fig.6.A)
Xla Wt + pqbp1(Fig.2.I)
Xla Wt + pqbp1 MO(Fig.2.C)
Xla Wt + pqbp1 MO(Fig.2.D)
Xla Wt + pqbp1 MO(Fig.2.E)
Xla Wt + pqbp1 MO(Fig.2.F)
Xla Wt + pqbp1 MO(Fig.2.H)
Xla Wt + pqbp1 MO(Fig.2.J,K)
Xla Wt + pqbp1 MO(Fig.3.A)
Xla Wt + pqbp1 MO(Fig.3.B)
Xla Wt + pqbp1 MO(Fig.3.C)
Xla Wt + pqbp1 MO(Fig.3.D)
Xla Wt + pqbp1 MO(Fig.4.C)
Xla Wt + pqbp1 MO(Fig.4.D)
Xla Wt + pqbp1 MO(Fig.5)
Xla Wt + pqbp1 MO(Fig.7.E)
Xla Wt + pqbp1 MO(Fig.S4)
Xla Wt + pqbp1 MO
Xla Wt + pqbp1 MO + wbp11 MO(Fig.4.D)
Xla Wt + pqbp1 MO + wbp11 MO(Fig.5)
Xla Wt + wbp11 MO(Fig.4.C)
Xla Wt + wbp11 MO(Fig.4.D)
Xla Wt + wbp11 MO(Fig.5)
Xla Wt + wnt8a + animal cap explant(Fig.6.A)
Xtr Wt + pqbp1 MO(Fig.S7.C)
Xtr Wt + pqbp1 MO(Fig.S7.C)
Xla Wt + nodal2 + animal cap explant(Fig.6.A)
Xla Wt + pqbp1(Fig.2.I)
Xla Wt + pqbp1 MO(Fig.2.C)
Xla Wt + pqbp1 MO(Fig.2.D)
Xla Wt + pqbp1 MO(Fig.2.E)
Xla Wt + pqbp1 MO(Fig.2.F)
Xla Wt + pqbp1 MO(Fig.2.H)
Xla Wt + pqbp1 MO(Fig.2.J,K)
Xla Wt + pqbp1 MO(Fig.3.A)
Xla Wt + pqbp1 MO(Fig.3.B)
Xla Wt + pqbp1 MO(Fig.3.C)
Xla Wt + pqbp1 MO(Fig.3.D)
Xla Wt + pqbp1 MO(Fig.4.C)
Xla Wt + pqbp1 MO(Fig.4.D)
Xla Wt + pqbp1 MO(Fig.5)
Xla Wt + pqbp1 MO(Fig.7.E)
Xla Wt + pqbp1 MO(Fig.S4)
Xla Wt + pqbp1 MO
Xla Wt + pqbp1 MO + wbp11 MO(Fig.4.D)
Xla Wt + pqbp1 MO + wbp11 MO(Fig.5)
Xla Wt + wbp11 MO(Fig.4.C)
Xla Wt + wbp11 MO(Fig.4.D)
Xla Wt + wbp11 MO(Fig.5)
Xla Wt + wnt8a + animal cap explant(Fig.6.A)
Xtr Wt + pqbp1 MO(Fig.S7.C)
Xtr Wt + pqbp1 MO(Fig.S7.C)
???attribute.lit??? ???displayArticles.show???
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Fig. 1. pqbp1 and wbp11 genes are similarly expressed in mesoderm and neural tissues during Xenopus development. (A) WISH detection of pqbp1 and wbp11 transcripts in 64-cell blastula, neurula and tailbud tadpole; lateral views except anterior (ant) view of neurula. (B-E) WISH on intact (C,E) or longitudinally bisected (B,D) embryos with probes indicated. Asterisks mark the dorsal blastopore lip. (B) pqbp1 transcripts are present in the animal pole ectoderm and marginal zone in early gastrula (stage 10.5), upper panel; sense probe, lower panel. (C) Expression of pqbp1 and chordin in gastrulae, stage 11.5. (D) Expression of pqbp1, wbp11, chordin and sox2 in late gastrulae, dorsal-posterior views. Expression of pqbp1 overlaps with chordin in dorsal/axial mesoderm (arrows) and with sox2 in anterior neurectoderm. (E) Expression of pqbp1 and ncam mRNA in the neural plate of early neurula embryos. Note pqbp1 expression is in a broader region than ncam. an, anterior neurectoderm; chd, chordin; S, pqbp1 sense probe. |
|
Fig. 2. Knockdown of PQBP1 causes defective embryo morphogenesis. (A) Design of three pqbp1 antisense morpholino oligonucleotides (MOs). MO1 (purple bar) targets the ATG start codon of pqbp1a and pqbp1b (with three nucleotide mismatches), while MOa and MOb (blue bars) target the 5′ UTRs of pqbp1 a and b, respectively. Identical nucleotides between pqbp1 a and b are indicated by black background. (B-F) Tailbud tadpole stage embryos injected bilaterally at the two-cell stage with 50 ng control (CT) or pqbp1 (PQ) MOs as indicated (embryos in F received 100 ng MOs in total). (G) Translation of C-terminal myc-tagged Xenopus PQBP1 (PQ-myc) was blocked by co-injection of pqbp1 MO1 but not control MO (CT). GFP mRNA co-injected as a negative control for MO targeting and loading control. (H) Phenotypes of tailbud stage embryos dorsally targeted with control (CT) or the indicated amount of pqbp1 MO1. (I) Overexpression of PQBP1 via injected mRNA (PQ) perturbs normal development. Left panel, wild-type embryo (stage 26); right panel, embryos injected dorsally with pqbp1 mRNA (2 ng) at the four-cell stage. (J,K) Gastrulation and neurulation defects are partially rescued by MO-resistant pqbp1 mRNA. PQ MO (30 ng) co-injected dorsally with 2 ng lacZ mRNA encoding β-galactosidase (β-gal), displayed perturbed gastrulation (arrowheads point to open blastopores) substantially rescued by co-injection of morpholino-resistant pqbp1 (2 ng) (J). Embryos injected with PQ MO and either 0.4 or 2 ng of pqbp1 mRNA scored for the following phenotypes (K): closed blastopore with complete neural folds (closed+com NF), closed blastopore with partial neural folds (closed+part NF), closed blastopore without neural folds (closed) or open blastopore (open). WT, wild type. |
|
Fig. 3. The effects of PQBP1 knockdown on embryonic mesoderm and neurectoderm. (A) Expression of the pan-mesodermal marker brachyury (bra) in late gastrula (stage 12.5) embryos injected with 20 ng pqbp1 MO1 into dorsal (D), ventral (V) or both (DV) blastomeres at the four-cell stage. Note lack of bra expression wherever the pqbp1 MO was injected (white brackets). (B) Expression of the dorsal (axial) mesoderm marker chordin in embryos injected dorsally with 20 ng of either control MO (CT MO) or pqbp1 MO1 (PQ MO1) at the four-cell stage. (C) Expression of neural marker ncam in uninjected (WT) or pqbp1 MO1-injected embryos targeted dorsally as in B. Lateral views with anterior to left. (D) Expression of the neural crest marker snail2 (slug) and the neural marker sox2 in neurula embryos (stage 19) injected in a single two-cell stage blastomere with 20 ng pqbp1 MO1 or control MO (CT) along with β-galactosidase lineage tracer (red). Dorsal views with anterior down. Perturbed neural folding is shown by differences between width of left and right neural folds (brackets). Loosely adherent sox2-positive cells, marked by arrowheads in the magnified view of the boxed area. WT, wild-type control embryos. |
|
Fig. 4. WBP11 knockdown resembles and enhances PQBP1 knockdown phenotypes. (A) WBP11 MO (blue arrow) targets the 5′ UTR of both X. laevis wbp11 homeologs. (B) Expression of endogenous WBP11 was blocked by injection of 40 ng wbp11 MO (WB MO) but not control MO (CT MO). Endogenous (red arrowhead) and overexpressed (black arrowhead) WBP11 were detected by western blot with anti-WBP11 antibodies. An asterisk indicates a non-specific band that, along with β-tubulin staining, controls for sample loading. (C) Tailbud stage embryos injected into two dorsal cells at the four-cell stage with 100 ng control MO (CT), a mix of pqbp1 MOa and MOb (50 ng each; PQ MO) or 50 ng wbp11 MO (WB MO). (D) Neurula (stage 20, anterior view) embryos injected dorsally at the four-cell stage (schematic drawing) with 75 ng control MO (CT), 25 ng wbp11 MO (WB), a mixture of pqbp1 MOa plus MOb (25 ng each; 50 ng total; PQ) or a combination of wbp11 and pqbp1 MOa and MOb (25 ng each; 75 ng total; PQ+WB). |
|
Fig. 5. Effects of PQBP1 and WBP11 knockdown on embryonic gene expression. qPCR performed on early gastrula (stage 10.5) morphant embryos injected bilaterally at the two-cell stage with 150 ng control (CT), 100 ng pqbp1 (PQ), 50 ng wbp11 (BP) or a combination of pqbp1 and wbp11 (PQ+BP) MOs (150 ng total). Values were plotted relative to the control cap signal and shown as mean±s.e.m of n=3 with Student's t-test to control embryos (CT) (*P<0.05 or **P<0.01). (A) Expression of general mesodermal markers brachyury (bra), antipodean (apod), sizzled, wnt8, fgf4, cdx4 and fgf8. (B) Expression of Spemann–Mangold organizer-specific markers, chordin, goosecoid, siamois and noggin. (C) Expression of early neural marker sox2. |
|
Fig. 6. Effects of PQBP1 knockdown on animal cap response to growth factors. (A,B) Two-cell embryos were injected into the animal pole with growth factor mRNAs and MOs, animal caps were cut at mid-blastula and harvested at the equivalent of early gastrula stage, followed by qPCR, as depicted (top). Results were analyzed and plotted as per Fig. 5. (A) Marker gene induction by Wnt8 (50 pg), BMP4 (500 pg) and Nodal2 (Xnr2; 100 pg) was not affected by PQBP1 knockdown (50 ng MO). There was no statistically significant difference between CT and PQBP1 MO-injected caps treated with each ligand (Student's t-test, n=3). (B) Marker gene induction by FGF4 was significantly reduced by PQBP1 knockdown (*P<0.05 or **P<0.01; Student's t-test, triplicate biological replicates). Animal caps were injected with fgf4 mRNA (1 pg) and either control MO (50 ng), pqbp1 MO1 (50 ng) or MOa+MOb (25 ng each). (C) Phosphorylation of MAPK (Erk) was induced in fgf4-injected animal caps, but blocked by co-injection of pqbp1 MO, either MO1 or MOa+MOb. The levels of β-tubulin and total MAPK protein did not change among these samples. |
|
Fig. 7. Alternative splicing pattern of fgfr2 exon 8a/b is altered by PQBP1 knockdown. (A) Alternative splicing incorporates either exon 8a or 8b into fgfr2 transcripts, which generates two isoforms of FGFR2: IIIb and IIIc, respectively (see text). Intron sizes (kb) indicated. (B,C) Sum total of qPCR measurements of fgfr2IIIb/c transcripts (B), and the relative levels of each splicing variant (C), on total RNA extracted from early gastrula (stage 10.5) morphant embryos bilaterally injected at the two-cell stage with MOs: 150 ng control (CT), 100 ng PQBP1 (PQ), 50 ng WBP11 (BP), or combined PQBP1 and WBP11 (PQ+BP) (150 ng total). Samples were prepared and analyzed as per Fig. 5 (*P<0.05 or **P<0.01; Student's t-test, n=3). (D) Semi-quantitative RT-PCR amplification products of alternative spliced exon 8a or 8b from embryos injected with morpholinos (as above). (E) Partial rescue of fgf4 expression in pqbp1 morphants (100 ng pqbp1 MO) by co-injection of 1 ng Xenopus fgfr2IIIc (*P<0.05; Student's t-test, n=3). |
|
Fig. S1. PQBP1 and WBP11 sequence comparisons. A. Alignment of PQBP1 protein sequences of human (Homo sapiens, Hs), mouse (Mus musculus, Mm), Xenopus laevis (Xl) homeologs a and b, zebrafish (Danio rerio, Dr) and Starlet sea anemone (Nematostella vectensis, Nv). Shading indicates homology (black 80–100%, grey 60–80%). WW: WW domain, PRD: polar amino acid rich domain, NLS: nuclear localization signal, CTD: C-terminal conserved domain. The additional polar amino acidrich tail highly conserved among species is marked by wavy line. B. Alignment of WBP11 protein sequences of human (Hs), mouse (Mm), Xenopus laevis (Xl) homeologs a and b, and zebrafish (Dr). Shading indicates homology (black 80–100%, grey 60–80%). |
|
Fig. S2. Expression profile of pqbp1 and wbp11 mRNA during embryogenesis. Total RNA extracted from indicated developmental stages of X. laevis was used for qPCR analysis. The results were normalized to ornithine decarboxylase (ODC) levels and plotted relative to the level measured in the stage 35 embryos (set as 1.0). |
|
Fig. S3. Expression of pqbp1 and wbp11 in neurula stage embryos. Whole mount in situ hybridization with indicated probes on embryos that were longitudinally sectioned (A) or crosssectioned (B) stage 18 embryos. S: sense probe of pqbp1. Both pqbp1 and wbp11 transcripts are localized to ventro-lateral neural tube cells (B). |
|
Fig. S4. Over-expression of PQBP1 inhibits normal specification and movement of dorsal mesoderm. Embryos at the end of gastrulation, stage 13, that had been dorsally injected at the 2-cell stage with 1 ng pqbp1 mRNA, were analyzed by in situ hybridization with brachyury (bra) and chordin (chd) probes. |
|
Fig. S5. Partial rescue of neural folding defects in PQBP1 morphants by pqbp1 mRNA. A. PQ MO1 (40 ng) was dorsally injected with either 2 ng b-galactosidase (b-gal) or pqbp1 (PQ) mRNA. B. Fraction of embryos displaying specific phenotypes: closed, partially closed or open neural folds (NF). |
|
Fig. S6. Xenopus WBP11 interacts with PQBP1. A. Co-immunoprecipitation (co-IP) of PQBP1 and WBP11 from COS1 cells transfected with HA-tagged PQBP1 (HA-PQ) and myc-tagged WBP11 (myc- WB). Cell lysates were immunoprecipitated (IP) with an anti-myc antibody, followed by immunoblotting with an anti-HA antibody to detect PQBP1 bound to WBP11, or vice versa. TCL: total Development | Supplementary Material cell lysate. B. Co-immunostaining of myc-tagged WBP11 (myc-WB) and HA-tagged PQBP1 (HA-PQ) expressed in COS1 cells. Nuclei were stained with DAPI. |
|
Fig. S7. Validation of pqbp1 knockdown effects on fgf4 and cdx4 expression in X. laevis and X. tropicalis embryos. Results were analyzed and plotted as described in Fig. 5. A-C. Expression of fgf4 and cdx4 was analyzed by qPCR. A. Either of the PQBP1 MOs (at 50 ng) reduced the expression of fgf4 and cdx4 in X. laevis morphant embryos, *P < 0.05 or **P < 0.01, with comparisons to control embryos (CT). B. Reduced fgf4 and cdx4 expression in embryos injected with 30 ng pqbp1 MOb at the 4-cell stage into the VMZ was rescued by co-injection of MOb-resistant PQBP1 mRNA (0.4 ng or 2 ng) but not control b-gal mRNA (-); *P < 0.05 or **P < 0.01, with comparisons to MO-only injected embryos (-). C. Analysis of PQBP1 knockdown in X. tropicalis embryos. X. tropicalis PQBP1 MO (20 ng) was bilaterally injected into embryos at the 2-cell stage, and phenotypes of stage-matched wild type (WT) embryo (left panel) and MO-injected embryos (middle panel) are shown. Expression of fgf4 and cdx4 were evaluated in WT and pqbp1 morphant X. tropicalis at the gastrula stage (right panel), as described in Fig. 5; *P < 0.05 or **P<0.01, with comparisons to control embryos (CT). |
|
Fig. S8. Expression profile of different FGF receptors in Xenopus embryos. A. Total RNA was extracted from early neurula stage embryos, followed by Lightcycler qPCR (27 cycles) with each receptor-specific primer set, and amplification products were visualized by gel electrophoresis. B. Expression profile of FGF receptors in morphant gastrula stage embryos by qPCR. Samples were prepared and analyzed as per Fig. 5. Relative fgfr expression levels were calculated from the “crossing point” (CP) of qPCR cycle numbers for each primer set, using a common standard curve generated from fgfr1IIIb control embryo cDNA dilution series, and normalized to levels of odc transcripts. Bar graphs indicate the relative expression level of receptor transcripts in embryos injected with 150 ng control (CT), 100 ng pqbp1 (PQ), 50 ng wbp11 (BP), and combined pqbp1 and wbp11 (PQ+BP) MOs. Mean values for triplicate biological experiments are plotted; bars indicate standard error. Note, although expression levels of fgfr1IIIc and fgfr3IIIb transcripts appear nearly zero, they were detected in gelbased and qPCR. |
|
pqbp1 (polyglutamine binding protein 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 7, lateral view, animal up. |
|
pqbp1 (polyglutamine binding protein 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 22, lateral view, anterior left, dorsal up. |
|
pqbp1 (polyglutamine binding protein 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 32, lateral view, anterior left, dorsal up. |
|
wbp11 (WW domain binding protein 11) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 7, lateral view, animal up. |
|
wbp11 (WW domain binding protein 11) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 22, lateral view, anterior left, dorsal up. |
|
wbp11 (WW domain binding protein 11) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 30, lateral view, anterior left, dorsal up. |
References [+] :
Alexandrova,
Smurf1 regulates neural patterning and folding in Xenopus embryos by antagonizing the BMP/Smad1 pathway.
2006, Pubmed,
Xenbase
Alexandrova, Smurf1 regulates neural patterning and folding in Xenopus embryos by antagonizing the BMP/Smad1 pathway. 2006, Pubmed , Xenbase
Amaya, FGF signalling in the early specification of mesoderm in Xenopus. 1993, Pubmed , Xenbase
Blunt, Overlapping expression and redundant activation of mesenchymal fibroblast growth factor (FGF) receptors by alternatively spliced FGF-8 ligands. 1997, Pubmed
Busch, Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington's disease. 2003, Pubmed
Callery, The ARID domain protein dril1 is necessary for TGF(beta) signaling in Xenopus embryos. 2005, Pubmed , Xenbase
Cossée, Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect. 2006, Pubmed
Deckert, Protein composition and electron microscopy structure of affinity-purified human spliceosomal B complexes isolated under physiological conditions. 2006, Pubmed
Delaune, Neural induction in Xenopus requires early FGF signalling in addition to BMP inhibition. 2005, Pubmed , Xenbase
Dichmann, fus/TLS orchestrates splicing of developmental regulators during gastrulation. 2012, Pubmed , Xenbase
Eswarakumar, Cellular signaling by fibroblast growth factor receptors. 2005, Pubmed
Eswarakumar, The IIIc alternative of Fgfr2 is a positive regulator of bone formation. 2002, Pubmed
Fisher, eFGF is required for activation of XmyoD expression in the myogenic cell lineage of Xenopus laevis. 2002, Pubmed , Xenbase
Fletcher, FGF8 spliceforms mediate early mesoderm and posterior neural tissue formation in Xenopus. 2006, Pubmed , Xenbase
Fletcher, The role of FGF signaling in the establishment and maintenance of mesodermal gene expression in Xenopus. 2008, Pubmed , Xenbase
Flynn, Whole gene duplication of the PQBP1 gene in syndrome resembling Renpenning. 2011, Pubmed
Fujii, VegT, eFGF and Xbra cause overall posteriorization while Xwnt8 causes eye-level restricted posteriorization in synergy with chordin in early Xenopus development. 2008, Pubmed , Xenbase
Germanaud, The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males. 2011, Pubmed
Guo, Distinct functions of the major Fgf8 spliceform, Fgf8b, before and during mouse gastrulation. 2007, Pubmed
Hajihosseini, A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes. 2001, Pubmed
Holzmann, Alternative Splicing of Fibroblast Growth Factor Receptor IgIII Loops in Cancer. 2012, Pubmed
Hughes, Evolution of duplicate genes in a tetraploid animal, Xenopus laevis. 1993, Pubmed , Xenbase
Ibrahimi, Understanding the molecular basis of Apert syndrome. 2005, Pubmed
Isaacs, eFGF regulates Xbra expression during Xenopus gastrulation. 1994, Pubmed , Xenbase
Isaacs, FGF4 regulates blood and muscle specification in Xenopus laevis. 2007, Pubmed , Xenbase
Ito, Knock-down of PQBP1 impairs anxiety-related cognition in mouse. 2009, Pubmed
Iwata, Fibroblast growth factor signaling in development of the cerebral cortex. 2009, Pubmed
Kalkan, Tumor necrosis factor-receptor-associated factor-4 is a positive regulator of transforming growth factor-beta signaling that affects neural crest formation. 2009, Pubmed , Xenbase
Kalscheuer, Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. 2003, Pubmed
Katoh, FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. 2009, Pubmed
Katoh, Cancer genomics and genetics of FGFR2 (Review). 2008, Pubmed
Kelleher, Fibroblast growth factor receptors, developmental corruption and malignant disease. 2013, Pubmed
Komuro, Npw38, a novel nuclear protein possessing a WW domain capable of activating basal transcription. 1999, Pubmed
Komuro, Association of two nuclear proteins, Npw38 and NpwBP, via the interaction between the WW domain and a novel proline-rich motif containing glycine and arginine. 1999, Pubmed
Lenski, Novel truncating mutations in the polyglutamine tract binding protein 1 gene (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another family with microcephaly. 2004, Pubmed
Liu, A variant of fibroblast growth factor receptor 2 (Fgfr2) regulates left-right asymmetry in zebrafish. 2011, Pubmed
Llorian, SIPP1, a novel pre-mRNA splicing factor and interactor of protein phosphatase-1. 2004, Pubmed
Llorian, Nucleocytoplasmic shuttling of the splicing factor SIPP1. 2005, Pubmed
Lubs, Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene. 2006, Pubmed
Makarova, A subset of human 35S U5 proteins, including Prp19, function prior to catalytic step 1 of splicing. 2004, Pubmed
Martínez-Garay, A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation. 2007, Pubmed
Marubuchi, Polyglutamine tract-binding protein-1 dysfunction induces cell death of neurons through mitochondrial stress. 2005, Pubmed
Mayshar, Fibroblast growth factor 4 and its novel splice isoform have opposing effects on the maintenance of human embryonic stem cell self-renewal. 2008, Pubmed
Mudò, The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain. 2009, Pubmed
Nicolaescu, Nature of the nuclear inclusions formed by PQBP1, a protein linked to neurodegenerative polyglutamine diseases. 2008, Pubmed
Okazawa, Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. 2002, Pubmed
Okuda, PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype. 2003, Pubmed
Ornitz, Receptor specificity of the fibroblast growth factor family. 1996, Pubmed
Qi, PQBP-1 is expressed predominantly in the central nervous system during development. 2005, Pubmed
Reuss, Fibroblast growth factors and their receptors in the central nervous system. 2003, Pubmed
Rice, Fgfr mRNA isoforms in craniofacial bone development. 2003, Pubmed
Stevenson, Renpenning syndrome comes into focus. 2005, Pubmed
Sudol, Molecular insights into the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1. 2012, Pubmed
Suga, Xenopus ADAMTS1 negatively modulates FGF signaling independent of its metalloprotease activity. 2006, Pubmed , Xenbase
Takeuchi, The roles of FGF signaling in germ cell migration in the mouse. 2005, Pubmed
Tamura, Drosophila PQBP1 regulates learning acquisition at projection neurons in aversive olfactory conditioning. 2010, Pubmed
Tapia, Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing. 2010, Pubmed
Teebi, Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2. 2002, Pubmed
Turner, The fibroblast growth factor family: neuromodulation of affective behavior. 2012, Pubmed
Wang, PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth. 2013, Pubmed
Waragai, PQBP-1/Npw38, a nuclear protein binding to the polyglutamine tract, interacts with U5-15kD/dim1p via the carboxyl-terminal domain. 2000, Pubmed
Waragai, PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival. 1999, Pubmed
Warzecha, Complex changes in alternative pre-mRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT). 2012, Pubmed
Warzecha, The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. 2009, Pubmed
Yoshimura, Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship. 2006, Pubmed
Zhang, Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. 2006, Pubmed
Zhang, Evidence that dim1 associates with proteins involved in pre-mRNA splicing, and delineation of residues essential for dim1 interactions with hnRNP F and Npw38/PQBP-1. 2000, Pubmed