Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation

Dev Cell. 2011 Apr 19;20(4):469-82. doi: 10.1016/j.devcel.2011.03.011.

Abstract

In vertebrate embryos, retinoic acid (RA) synthesized in the mesoderm by Raldh2 emanates to the hindbrain neuroepithelium, where it induces anteroposterior (AP)-restricted Hox expression patterns and rhombomere segmentation. However, how appropriate spatiotemporal RA activity is generated in the hindbrain is poorly understood. By analyzing Pbx1/Pbx2 and Hoxa1/Pbx1 null mice, we found that Raldh2 is itself under the transcriptional control of these factors and that the resulting RA-deficient phenotypes can be partially rescued by exogenous RA. Hoxa1-Pbx1/2-Meis2 directly binds a specific regulatory element that is required to maintain normal Raldh2 expression levels in vivo. Mesoderm-specific Xhoxa1 and Xpbx1b knockdowns in Xenopus embryos also result in Xraldh2 downregulation and hindbrain defects similar to mouse mutants, demonstrating conservation of this Hox-Pbx-dependent regulatory pathway. These findings reveal a feed-forward mechanism linking Hox-Pbx-dependent RA synthesis during early axial patterning with the establishment of spatially restricted Hox-Pbx activity in the developing hindbrain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1
  • Aldehyde Oxidase / genetics
  • Aldehyde Oxidase / metabolism
  • Aldehyde Oxidoreductases / genetics
  • Aldehyde Oxidoreductases / metabolism
  • Animals
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Pregnancy
  • Retinal Dehydrogenase
  • Rhombencephalon / embryology*
  • Rhombencephalon / metabolism*
  • Tretinoin / metabolism*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis / embryology
  • Xenopus laevis / metabolism

Substances

  • Aldehyde Dehydrogenase 1
  • Homeodomain Proteins
  • Xenopus Proteins
  • Tretinoin
  • Aldehyde Oxidoreductases
  • RALDH2 protein, mouse
  • Retinal Dehydrogenase
  • aldh1a2 protein, Xenopus
  • Aldehyde Oxidase