title: Genetic and Molecular Analyses indicate independent effects of TGIFs on Nodal and Gli3 in neural tube patterning.
abstract: Holoprosencephaly (HPE) is a prevalent craniofacial developmental disorder that has both genetic and environmental causes. The gene encoding TG-interacting factor 1 (TGIF1) is among those that are routinely screened in HPE patients. However, the mechanisms by which TGIF1 variants cause HPE are not fully understood. TGIF1 is a transcriptional repressor that limits the output of the Transforming Growth Factor ß (TGFß)/Nodal signaling pathway, and HPE in patients with TGIF1 variants has been suggested to be due to increased Nodal signaling. Mice lacking both Tgif1 and its paralog, Tgif2, have HPE, and embryos lacking Tgif function do not survive past mid-gestation. Here, we show that in the presence of a Nodal heterozygous mutation, proliferation defects are rescued and a proportion of embryos lacking all Tgif function survive to late gestation. However, these embryos have a classic HPE phenotype, suggesting that this is a Nodal-independent effect of Tgif loss of function. Further, we show that the Gli3 gene is a direct target for repression by Tgifs, independent of TGFß/Nodal signaling, consistent with Tgif mutations causing HPE via Nodal-independent effects on the Sonic Hedgehog (Shh) pathway. Based on this work, we propose a model for distinct functions of Tgifs in the Nodal and Shh/Gli3 pathways during forebrain development.
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, 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, VA, 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, VA, 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, VA, USA.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Carlton
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
authors.forename: Arkadi
authors.initials: A
authors.lastname: Manukyan
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA, 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, VA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wotton
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D055457:Nodal Protein / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D012097:Repressor Proteins; C465570:Shh protein, mouse; C490797:Tgif1 protein, mouse; D000074290:Zinc Finger Protein Gli3