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Dev Cell
2011 Apr 19;204:469-82. doi: 10.1016/j.devcel.2011.03.011.
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Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation.
Vitobello A, Ferretti E, Lampe X, Vilain N, Ducret S, Ori M, Spetz JF, Selleri L, Rijli FM.
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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.
Fig.4. Mesoderm-Specific Xpbx1 and Xhoxa1 Knockdown in Xenopus Embryos(A) Diagram of marginal zone V2.2 Xenopus blastomere injection at 16-cell stage, and fate of injected blastomere in stage 17 neurula.(B) Whole-mount detection of RFP in left V2.2 blastomere-injected embryo.(C) Merge of bright field and fluorescence pictures of the embryo in (B).(D) Cross-section showing selective RFP labeling in somites (s) and lateral plate mesoderm (lpm).(E–I) Whole-mount double in situ hybridization for Xraldh2 and Xkrox20 in control-MO (E), Xpbx1b-MO (F and G), and Xpbx1b-MO;Xhoxa1-MO (H and I) left V2.2 blastomere-injected embryos.(J) Nuclear-salmon-gal staining (red cells) of Xpbx1b-MO;Xhoxa1-MO V2.2-injected embryos indicate morphant cell localization in mesoderm. Xkrox20 expression shows r3* posteriorization and r5* loss on the injected side.(K and L) Correlation between Xraldh2 downregulation and hindbrain phenotype in Xpbx1b-MO and Xpbx1b;Xhoxa1-MO injected embryos (mosaic plots). Relative phenotype severity is color-coded. Phenotype frequencies (y axis) are compared to levels of Raldh2 (x axis). Synergistic action of Xpbx1b-MO;Xhoxa1-Mo results in rising the frequencies of Xraldh2 severe reduction or loss and hindbrain patterning defects. MO, morpholino; r, rhombomere; RFP, Red Fluorescent Protein.See also Figure S2.
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