title: Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l.
abstract: Mouse embryos conditionally lacking Tgif1 and Tgif2 have holoprosencephaly and defects in left-right asymmetry. To identify pathways affected by loss of Tgif function during embryogenesis, we performed transcriptome profiling on whole mouse embryos. Among the genes with altered expression in embryos lacking Tgifs were a number with links to cilium function. One of these,Evi5l, encodes a RabGAP that is known to block the formation of cilia when overexpressed.Evi5lexpression is increased inTgif1;Tgif2-null embryos and in double-null mouse embryo fibroblasts (MEFs). Knockdown of Tgifs in a human retinal pigment epithelial cell line also increasedEVI5Lexpression. We show that TGIF1 binds to a conserved consensus TGIF site 5' of the human and mouseEvi5lgenes and represses Evi5l expression. In primary MEFs lacking both Tgifs, the number of cells with primary cilia was significantly decreased, and we observed a reduction in the transcriptional response to Shh pathway activation. Reducing Evi5l expression in MEFs lacking Tgifs resulted in a partial restoration of cilium numbers and in the transcriptional response to activation of the Shh pathway. In summary, this work shows that Tgifs regulate ciliogenesis and suggests that Evi5l mediates at least part of this effect.
authors.affiliation: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Anoush E
authors.initials: AE
authors.lastname: Anderson
authors.affiliation: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Melhuish
authors.affiliation: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Anant
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Sutherland
authors.affiliation: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA dw2p@virginia.edu.
authors.forename: David
authors.initials: D
authors.lastname: Wotton
mesh_terms: D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D063990:Gene Ontology; D053823:Hedgehog Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C000621117:EVI5L protein, human; C000621118:Evi5l protein, mouse; D020690:GTPase-Activating Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C465570:Shh protein, mouse; C505201:TG-interacting factor 2, mouse; C097504:TGIF1 protein, human; C414585:TGIF2 protein, human; D014157:Transcription Factors
keywords: Evi5l; Tgif; Tgif1; Tgif2; cilium; regulation of gene expression; transcription factors