title: The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling.
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.
authors.affiliation: Department of Biochemistry and Cell Biology, Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794-5215, USA.
authors.forename: Yasuno
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Biochemistry and Cell Biology, Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794-5215, USA gerald.h.thomsen@stonybrook.edu.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Thomsen
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008648:Mesoderm / Q000378:metabolism*; D060172:Morpholinos / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology*
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D060172:Morpholinos; D009419:Nerve Tissue Proteins; C000592999:PQBP1 protein, Xenopus; D016601:RNA-Binding Proteins; D029867:Xenopus Proteins; D005346:Fibroblast Growth Factors
keywords: Alternative splicing; FGF; FGF receptor; Mesoderm; Neural; PQBP1; Renpenning syndrome; WBP11; Xenopus