Transcriptional regulation of the homeobox gene Mixl1 by TGF-beta and FoxH1

Biochem Biophys Res Commun. 2005 Aug 12;333(4):1361-9. doi: 10.1016/j.bbrc.2005.06.044.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / physiology
  • DNA-Binding Proteins / metabolism*
  • Forkhead Transcription Factors
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nodal Protein
  • Signal Transduction / physiology
  • Transcription Factors / metabolism*
  • Transcriptional Activation / physiology*
  • Transforming Growth Factor beta / metabolism*

Substances

  • DNA-Binding Proteins
  • FOXH1 protein, human
  • Forkhead Transcription Factors
  • Foxh1 protein, mouse
  • Homeodomain Proteins
  • MIXL1 protein, human
  • Mixl1 protein, mouse
  • NODAL protein, human
  • Nodal Protein
  • Nodal protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta