title: Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development.
abstract: Mixl1 is a member of the Mix/Bix family of paired-like homeodomain proteins and is required for proper axial mesendoderm morphogenesis and endoderm formation during mouse development. Mix/Bix proteins are transcription factors that function in Nodal-like signaling pathways and are themselves regulated by Nodal. Here, we show that Foxh1 forms a DNA-binding complex with Smads to regulate transforming growth factor beta (TGFbeta)/Nodal-dependent Mixl1 gene expression. Whereas Foxh1 is commonly described as a transcriptional activator, we observed that Foxh1-null embryos exhibit expanded and enhanced Mixl1 expression during gastrulation, indicating that Foxh1 negatively regulates expression of Mixl1 during early mouse embryogenesis. We demonstrate that Foxh1 associates with the homeodomain-containing protein Goosecoid (Gsc), which in turn recruits histone deacetylases to repress Mixl1 gene expression. Ectopic expression of Gsc in embryoid bodies represses endogenous Mixl1 expression and this effect is dependent on Foxh1. As Gsc is itself induced in a Foxh1-dependent manner, we propose that Foxh1 initiates positive and negative transcriptional circuits to refine cell fate decisions during gastrulation.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Luisa
authors.initials: L
authors.lastname: Izzi
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Silvestri
authors.forename: Ingo
authors.initials: I
authors.lastname: von Both
authors.forename: Etienne
authors.initials: E
authors.lastname: Labbé
authors.forename: Lise
authors.initials: L
authors.lastname: Zakin
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Liliana
authors.initials: L
authors.lastname: Attisano
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051956:Goosecoid Protein / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D055457:Nodal Protein; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D051956:Goosecoid Protein; C497993:Gsc protein, mouse; D018398:Homeodomain Proteins; C464781:Mixl1 protein, mouse; C526007:NODAL protein, human; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D028341:Activins; D006655:Histone Deacetylases