Transcriptional regulation of the homeobox gene Mixl1 by TGF-beta and FoxH1.
Mixl1 is a paired-type homeodomain protein that plays a crucial role in morphogenesis and endoderm differentiation in the murine embryo. To understand how Mixl1 directs embryogenesis, we studied the regulation of Mixl1 expression at a transcriptional level. In HepG2 cells, a genomic fragment encompassing the Mixl1 promoter conferred strong TGF-beta-induced transcription that was dependent on the presence of the DNA-binding protein FoxH1. Further analysis of the Mixl1 promoter identified a proximal response element (PRE) containing SMAD- and FoxH1-binding sites required for TGF-beta responsiveness. The PRE was also responsive to signalling by Nodal, a TGF-beta ligand required for normal embryonic patterning. These results demonstrate for the first time a functional role for TGF-beta ligands in regulation of mammalian Mixl1, identify FoxH1 as an essential transcriptional co-activator, and implicate Nodal as the embryonic regulator of Mixl1 in mesendoderm morphogenesis.
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville 3050, Vic., Australia. hart@wehi.edu.au
Adam H
AH
Hart
Tracy A
TA
Willson
Michael
M
Wong
Karen
K
Parker
Lorraine
L
Robb
D000818:Animals; D019521:Body Patterning / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D055457:Nodal Protein; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; C510350:FOXH1 protein, human; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D018398:Homeodomain Proteins; C499230:MIXL1 protein, human; C464781:Mixl1 protein, mouse; C526007:NODAL protein, human; D055457:Nodal Protein; C526008:Nodal protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta