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

Dev Cell. 2008 Mar;14(3):411-23. doi: 10.1016/j.devcel.2008.01.004.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • Cell Line
  • DNA / genetics
  • DNA / metabolism
  • Enhancer Elements, Genetic
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Developmental
  • Genomics
  • Humans
  • In Situ Hybridization
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Prosencephalon / embryology*
  • Prosencephalon / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retinal Dehydrogenase
  • Signal Transduction
  • Smad Proteins / genetics
  • Smad Proteins / metabolism*
  • Transfection
  • Tretinoin / metabolism*

Substances

  • Forkhead Transcription Factors
  • Foxh1 protein, mouse
  • Isoenzymes
  • RNA, Messenger
  • Smad Proteins
  • Tretinoin
  • DNA
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase