Abstract
Foxh1, a Smad DNA-binding partner, mediates TGFbeta-dependent gene expression during early development. Few Foxh1 targets are known. Here, we describe a genome-wide approach that we developed that couples systematic mapping of a functional Smad/Foxh1 enhancer (SFE) to Site Search, a program used to search annotated genomes for composite response elements. Ranking of SFEs that are positionally conserved across species yielded a set of genes enriched in Foxh1 targets. Analysis of top candidates, such as Hesx1, Lgr4, Lmo1, Fgf8, and members of the Aldh1a subfamily, revealed that Foxh1 initiates a transcriptional regulatory network within the developing anterior neuroectoderm. The Aldh1a family is required for retinoic acid (RA) synthesis, and, in Foxh1 mutants, expression of Aldh1a1, -2, and -3 and activation of a RA-responsive transgenic reporter is abolished in anterior structures. Integrated mapping of a developmental transcription factor network thus reveals a key role for Foxh1 in patterning and initiating RA signaling in the forebrain.
Original language | English |
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Pages (from-to) | 411-423 |
Number of pages | 13 |
Journal | Developmental Cell |
Volume | 14 |
Issue number | 3 |
DOIs | |
Publication status | Published - 11 Mar 2008 |
Keywords
- Aldehyde Dehydrogenase
- Animals
- Base Sequence
- Binding Sites
- Cell Line
- DNA
- Enhancer Elements, Genetic
- Forkhead Transcription Factors
- Gene Expression Regulation, Developmental
- Genomics
- Humans
- In Situ Hybridization
- Isoenzymes
- Mice
- Mice, Knockout
- Mice, Transgenic
- Models, Biological
- Prosencephalon
- RNA, Messenger
- Signal Transduction
- Smad Proteins
- Transfection
- Tretinoin