title: Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vitobello
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Xavier
authors.initials: X
authors.lastname: Lampe
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vilain
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ducret
authors.forename: Michela
authors.initials: M
authors.lastname: Ori
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Spetz
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Rijli
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D042931:Aldehyde Oxidase / Q000235:genetics / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011247:Pregnancy; D050697:Retinal Dehydrogenase; D012249:Rhombencephalon / Q000196:embryology* / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D029867:Xenopus Proteins; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; D000080924:Aldehyde Dehydrogenase 1 Family; C470579:RALDH2 protein, mouse; D050697:Retinal Dehydrogenase; C493756:aldh1a2 protein, Xenopus; D042931:Aldehyde Oxidase