Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development.
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.
Izzi
Luisa
L
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Silvestri
Cristoforo
C
von Both
Ingo
I
Labbé
Etienne
E
Zakin
Lise
L
Wrana
Jeffrey L
JL
Attisano
Liliana
L
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
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