Genome-wide identification of Smad/Foxh1 targets reveals a role for Foxh1 in retinoic acid regulation and forebrain development

Cristoforo Silvestri, Masahiro Narimatsu, Ingo von Both, Yongmei Liu, Nicholas B. J. Tan, Luisa Izzi, Peter McCaffery, Jeffrey L. Wrana, Liliana Attisano

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 languageEnglish
Pages (from-to)411-423
Number of pages13
JournalDevelopmental Cell
Volume14
Issue number3
DOIs
Publication statusPublished - 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

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