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  • Review Article
  • Published:

Retinoic acid in development: towards an integrated view

Nature Reviews Genetics volume 9, pages 541–553 (2008)Cite this article

Key Points

  • Retinoic acid (RA), the active form of vitamin A, is a small lipophilic molecule that acts as a signalling molecule in vertebrates by binding to nuclear receptors (heterodimers of RA receptors and retinoid X receptors; RAR–RXR) and regulating the transcriptional activity of various target genes.

  • The distribution of RA is tightly controlled in embryonic tissues. Its synthesis from inactive precursors (retinol or beta-carotene) is mediated by retinaldehyde dehydrogenases 1 to 3 (RALDH1 to RALDH3), and a group of cytochrome P450s (the cytochrome P450 26 enzymes CYP26A1 to CYP26C1) trigger its tissue-specific catabolism. Both types of enzymes are often expressed according to mutually exclusive, complementary patterns.

  • Although there is clear evidence that RA acts as a short-range signal across tissue layers, its role as a long-range, concentration-dependent morphogen has long been debated. Recent work provided evidence for a robust RA gradient in the prospective hindbrain of the zebrafish embryo, shaped by the fibroblast growth factor (FGF)-dependent control of CYP26A1 activity.

  • Although the most anterior (prospective head) embryonic cells are initially protected from RA signalling by CYP26A1 and CYP26C1 activities, eventually RA is produced by RALDH2 and RALDH3 in the rostral forebrain neuroepithelium and surface ectoderm, and is necessary for proper growth and patterning of the embryonic forebrain and optic vesicle.

  • During extension of the body axis, a caudal pool of progenitor and/or stem cells is maintained by FGF8 signalling, and RA produced by RALDH2 in differentiating mesodermal tissues (including the somites) acts in an antagonist manner, promoting neurogenesis and regulating ventral patterning genes in the prospective spinal cord. RA is also necessary for 'buffering' left–right asymmetric embryonic signals, thus ensuring a symmetrical progression of mesodermal segmentation, that is, somitogenesis.

  • Various functions have been ascribed to RA with respect to heart development, recent work implicated it in the proper restriction of the cardiac progenitor cell pool in the early zebrafish embryo, and in the mouse in the formation and proper contribution of the 'second heart field' to the developing heart tube.

  • Cross-talk between RA and other embryonic signals are being unravelled. Contrasting with the functional antagonism between RA and FGF during caudal axis extension, during organ outgrowth RA was often found to have a positive effect on the induction (or the maintenance of appropriate levels) of FGF(s) involved in these processes. RA is also indispensable for cells to efficiently respond to the sonic hedgehog (SHH) signal, probably by controlling some downstream effectors of this pathway.

  • RA signalling has been detected in regions of the adult rodent brain containing neural stem cell niches, and some studies have correlated decreased RA levels with neurodegenerative diseases, such as amyotrophic lateral sclerosis, or Alzheimer disease. Retinoids are already used in therapy, and a better understanding of the effects of RA — in combination with other signalling factors — in stem cell populations might lead to novel therapeutic avenues.

Abstract

Retinoic acid (RA) has complex and pleiotropic functions during vertebrate development. Recent work in several species has increased our understanding of the roles of RA as a signalling molecule. These functions rely on a tight control of RA distribution within embryonic tissues through the combined action of synthesizing and metabolizing enzymes, possibly leading to diffusion gradients. Also important is the switching of nuclear receptors from a transcriptionally repressing state to an activating state. In addition, cross-talk with other key embryonic signals, especially fibroblast growth factors (FGFs) and sonic hedgehog (SHH), is being uncovered. Some of these functions could be maintained throughout the life of an organism to regulate cell-lineage decisions and/or the differentiation of stem cell populations, highlighting possibilities for regenerative medicine.

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Figure 1: Regulation of retinoid signalling in embryonic cells.
Figure 2: Sequential phases of retinoic acid requirement during development of head structures.
Figure 3: Molecular interactions controlling growth and differentiation of the elongating embryonic axis.
Figure 4: Retinoic acid-dependent molecular interactions control organ growth.

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References

  1. Thaller, C. & Eichele, G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature 327, 625–628 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Wilson, J. G., Roth, C. B. & Warkany, J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am. J. Anat. 92, 189–217 (1953).

    Article  CAS  PubMed  Google Scholar 

  3. Mark, M., Ghyselinck, N. B. & Chambon, P. Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu. Rev. Pharmacol. Toxicol. 46, 451–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Kastner, P. et al. Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development 124, 313–326 (1997).

    CAS  PubMed  Google Scholar 

  5. Durston, A. J. et al. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340, 140–144 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Simeone, A. et al. Retinoic acid induces stage-specific antero–posterior transformation of rostral central nervous system. Mech. Dev. 51, 83–98 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Maden, M. Retinoid signalling in the development of the central nervous system. Nature Rev. Neurosci. 3, 843–853 (2002).

    Article  CAS  Google Scholar 

  8. White, R. J., Nie, Q., Lander, A. D. & Schilling, T. F. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biol. 5, e304 (2007). An appealing model is proposed that accounts for the robustness of a RA gradient established by adverse effects of RA and FGF on cyp26a1 regulation, which would operate during hindbrain development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maden, M. Retinoids and spinal cord development. J. Neurobiol. 66, 726–738 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nature Rev. Neurosci. 8, 755–765 (2007).

    Article  CAS  Google Scholar 

  11. Maden, M. Retinoic acid and limb regeneration — a personal view. Int. J. Dev. Biol. 46, 883–886 (2002).

    PubMed  Google Scholar 

  12. Schneider, R. A., Hu, D., Rubenstein, J. L., Maden, M. & Helms, J. A. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development 128, 2755–2767 (2001).

    CAS  PubMed  Google Scholar 

  13. Halilagic, A. et al. Retinoids control anterior and dorsal properties in the developing forebrain. Dev. Biol. 303, 362–375 (2007). Two animal models were combined in this study to investigate functional interactions between RA, FGF, SHH and Wnt signals during forebrain and eye development.

    Article  CAS  PubMed  Google Scholar 

  14. Ribes, V., Wang, Z., Dollé, P. & Niederreither, K. Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development 133, 351–361 (2006). The involvement of RA in regulating forebrain growth and patterning and in maintaining proper FGF and sonic hedgehog signalling is genetically demonstrated in this study.

    Article  CAS  PubMed  Google Scholar 

  15. Matt, N. et al. Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. Development 132, 4789–4800 (2005). In this study, and in reference 16, a combination of murine gene knockouts was used to investigate the consequences of defective RA signalling during early eye development.

    Article  CAS  PubMed  Google Scholar 

  16. Molotkov, A., Molotkova, N. & Duester, G. Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning. Development 133, 1901–1910 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Romand, R., Dollé, P. & Hashino, E. Retinoid signaling in inner ear development. J. Neurobiol. 66, 687–704 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Niederreither, K. et al. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development 128, 1019–1031 (2001).

    CAS  PubMed  Google Scholar 

  19. Wang, Z., Dollé, P., Cardoso, W. V. & Niederreither, K. Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives. Dev. Biol. 297, 433–445 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Batourina, E. et al. Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nature Genet. 27, 74–78 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Martin, M. et al. Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Dev. Biol. 284, 399–411 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Kawaguchi, R. et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315, 820–825 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Bouillet, P. et al. Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein. Mech. Dev. 63, 173–186 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Pasutto, F. et al. Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am. J. Hum. Genet. 80, 550–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Molotkov, A. et al. Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proc. Natl Acad. Sci. USA 99, 5337–5342 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sandell, L. L. et al. RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev. 21, 1113–1124 (2007). Through a random mutagenesis screen, this work demonstrated the involvement of a specific retinol dehydrogenase (RDH10) in mouse embryogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cammas, L., Romand, R., Fraulob, V., Mura, C. & Dollé, P. Expression of the murine retinol dehydrogenase 10 (Rdh10) gene correlates with many sites of retinoid signalling during embryogenesis and organ differentiation. Dev. Dyn. 236, 2899–2908 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Dupe, V. et al. A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc. Natl Acad. Sci. USA 100, 14036–14041 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Niederreither, K., Subbarayan, V., Dollé, P. & Chambon, P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genet. 21, 444–448 (1999). The first demonstration of pleiotropic embryonic defects, manifesting shortly after gastrulation, through loss of function of a single murine RA-synthesizing enzyme is presented in this paper.

    Article  CAS  PubMed  Google Scholar 

  30. Rossant, J., Zirngibl, R., Cado, D., Shago, M. & Giguere, V. Expression of a retinoic acid response element–hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes Dev. 5, 1333–1344 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Haskell, G. T. & LaMantia, A. S. Retinoic acid signaling identifies a distinct precursor population in the developing and adult forebrain. J. Neurosci. 25, 7636–7647 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Niederreither, K., McCaffery, P., Drager, U. C., Chambon, P. & Dollé, P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech. Dev. 62, 67–78 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Mic, F. A., Haselbeck, R. J., Cuenca, A. E. & Duester, G. Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development 129, 2271–2282 (2002).

    CAS  PubMed  Google Scholar 

  34. Mic, F. A., Sirbu, I. O. & Duester, G. Retinoic acid synthesis controlled by Raldh2 is required early for limb bud initiation and then later as a proximodistal signal during apical ectodermal ridge formation. J. Biol. Chem. 279, 26698–26706 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Niederreither, K., Vermot, J., Schuhbaur, B., Chambon, P. & Dollé, P. Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 127, 75–85 (2000).

    CAS  PubMed  Google Scholar 

  36. Niederreither, K., Vermot, J., Schuhbaur, B., Chambon, P. & Dollé, P. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development 129, 3563–3574 (2002).

    CAS  PubMed  Google Scholar 

  37. Sirbu, I. O. & Duester, G. Retinoic-acid signalling in node ectoderm and posterior neural plate directs left-right patterning of somitic mesoderm. Nature Cell Biol. 8, 271–277 (2006). This work, together with references 38, 40 and 78, revealed an important role of RA in controlling the synchrony of somitogenesis along the left and right side of the embryo.

    Article  CAS  PubMed  Google Scholar 

  38. Vermot, J. et al. Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science 308, 563–566 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Gale, E., Zile, M. & Maden, M. Hindbrain respecification in the retinoid-deficient quail. Mech. Dev. 89, 43–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Vermot, J. & Pourquié, O. Retinoic acid coordinates somitogenesis and left–right patterning in vertebrate embryos. Nature 435, 215–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Simões-Costa, M. S., Azambuja, A. P. & Xavier-Neto, J. The search for non-chordate retinoic acid signaling: lessons from chordates. J. Exp. Zool. B Mol. Dev. Evol. 310, 54–72 (2006).

    Google Scholar 

  42. Lubzens, E., Lissauer, L., Levavi-Sivan, B., Avarre, J. C. & Sammar, M. Carotenoid and retinoid transport to fish oocytes and eggs: what is the role of retinol binding protein? Mol. Aspects Med. 24, 441–457 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Lampert, J. M. et al. Provitamin A conversion to retinal via the beta, beta-carotene-15,15′-oxygenase (bcox) is essential for pattern formation and differentiation during zebrafish embryogenesis. Development 130, 2173–2186 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Yan, W. et al. Cloning and characterization of a human beta, beta-carotene-15,15′-dioxygenase that is highly expressed in the retinal pigment epithelium. Genomics 72, 193–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Mora, O. et al. A potential role for beta-carotene in avian embryonic development. Int. J. Vitam. Nutr. Res. 74, 116–122 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. von Lintig, J. & Vogt, K. Vitamin A formation in animals: molecular identification and functional characterization of carotene cleaving enzymes. J. Nutr. 134, 251S–256S (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, X. D. et al. Beta-oxidation in rabbit liver in vitro and in the perfused ferret liver contributes to retinoic acid biosynthesis from beta-apocarotenoic acids. J. Biol. Chem. 271, 26490–26498 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Chambers, D., Wilson, L., Maden, M. & Lumsden, A. RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1. Development 134, 1369–1383 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Stoilov, I., Rezaie, T., Jansson, I., Schenkman, J. B. & Sarfarazi, M. Expression of cytochrome P4501b1 (Cyp1b1) during early murine development. Mol. Vis. 10, 629–636 (2004).

    CAS  PubMed  Google Scholar 

  50. Hollander, D. A. et al. Genotype and phenotype correlations in congenital glaucoma: CYP1B1 mutations, goniodysgenesis, and clinical characteristics. Am. J. Ophthalmol. 142, 993–1004 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. White, J. A. et al. Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. J. Biol. Chem. 271, 29922–29927 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. MacLean, G. et al. Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development. Mech. Dev. 107, 195–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Tahayato, A., Dollé, P. & Petkovich, M. Cyp26C1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development. Gene Expr. Patterns 3, 449–454 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Pijnappel, W. W. et al. The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature 366, 340–344 (1993).

    Article  CAS  PubMed  Google Scholar 

  55. Niederreither, K. et al. Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nature Genet. 31, 84–88 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Abu-Abed, S. et al. The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 15, 226–240 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sakai, Y. et al. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio–posterior axis within the mouse embryo. Genes Dev. 15, 213–225 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yashiro, K. et al. Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev. Cell 6, 411–422 (2004). This is an outstanding study on the consequences of deregulated RA signalling through loss of Cyp26b1 function in the developing mouse limbs.

    Article  CAS  PubMed  Google Scholar 

  59. Glover, J. C., Renaud, J. S. & Rijli, F. M. Retinoic acid and hindbrain patterning. J. Neurobiol. 66, 705–725 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Hernandez, R. E., Putzke, A. P., Myers, J. P., Margaretha, L. & Moens, C. B. Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development. Development 134, 177–187 (2007). In this paper, a combination of loss-of-function approaches in zebrafish demonstrated the combinatorial roles of the three CYP26 enzymes during hindbrain patterning and cephalic development.

    Article  CAS  PubMed  Google Scholar 

  61. Sirbu, I. O., Gresh, L., Barra, J. & Duester, G. Shifting boundaries of retinoic acid activity control hindbrain segmental gene expression. Development 132, 2611–2622 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Uehara, M. et al. CYP26A1 and CYP26C1 cooperatively regulate anterior–posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse. Dev. Biol. 302, 399–411 (2007). By combining murine gene knockouts, these authors demonstrate the importance of regulated RA catabolism in the rostral head region of the early embryo.

    Article  CAS  PubMed  Google Scholar 

  63. Maves, L. & Kimmel, C. B. Dynamic and sequential patterning of the zebrafish posterior hindbrain by retinoic acid. Dev. Biol. 285, 593–605 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Koide, T., Downes, M., Chandraratna, R. A., Blumberg, B. & Umesono, K. Active repression of RAR signaling is required for head formation. Genes Dev. 15, 2111–2121 (2001). Several approaches were used to demonstrate that RA receptors, functioning as unliganded, transcriptional repressors in the prospective head, are necessary at pregastrulation and gastrulation stages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Beddington, R. S. & Robertson, E. J. Anterior patterning in mouse. Trends Genet. 14, 277–284 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Weinstein, D. C. & Hemmati-Brivanlou, A. Neural induction. Annu. Rev. Cell Dev. Biol. 15, 411–433 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Emoto, Y., Wada, H., Okamoto, H., Kudo, A. & Imai, Y. Retinoic acid-metabolizing enzyme Cyp26a1 is essential for determining territories of hindbrain and spinal cord in zebrafish. Dev. Biol. 278, 415–427 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Ribes, V., Fraulob, V., Petkovich, M. & Dollé, P. The oxidizing enzyme CYP26a1 tightly regulates the availability of retinoic acid in the gastrulating mouse embryo to ensure proper head development and vasculogenesis. Dev. Dyn. 236, 644–653 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Halilagic, A., Zile, M. H. & Studer, M. A novel role for retinoids in patterning the avian forebrain during presomite stages. Development 130, 2039–2050 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Wagner, E., McCaffery, P. & Drager, U. C. Retinoic acid in the formation of the dorsoventral retina and its central projections. Dev. Biol. 222, 460–470 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Mic, F. A., Molotkov, A., Molotkova, N. & Duester, G. Raldh2 expression in optic vesicle generates a retinoic acid signal needed for invagination of retina during optic cup formation. Dev. Dyn. 231, 270–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Diez del Corral, R. et al. Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron 40, 65–79 (2003). This study provided important clues about a functional antagonism between RA and FGF signalling during body-axis extension and spinal-cord differentiation.

    Article  CAS  PubMed  Google Scholar 

  73. Diez del Corral, R., Breitkreuz, D. N. & Storey, K. G. Onset of neuronal differentiation is regulated by paraxial mesoderm and requires attenuation of FGF signalling. Development 129, 1681–1691 (2002).

    PubMed  Google Scholar 

  74. Diez del Corral, R. & Storey, K. G. Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis. Bioessays 26, 857–869 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Olivera-Martinez, I. & Storey, K. G. Wnt signals provide a timing mechanism for the FGF-retinoid differentiation switch during vertebrate body axis extension. Development 134, 2125–2135 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Dubrulle, J. & Pourquié, O. Coupling segmentation to axis formation. Development 131, 5783–5793 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Wahl, M. B., Deng, C., Lewandoski, M. & Pourquié, O. FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis. Development 134, 4033–4041 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Kawakami, Y., Raya, A., Raya, R. M., Rodríguez-Esteban, C. & Belmonte, J. C. Retinoic acid signalling links left–right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature 435, 165–171 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Dequeant, M. L. & Pourquié, O. Segmental patterning of the vertebrate embryonic axis. Nature Rev. Genet. 9, 370–382 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Boettger, T., Wittler, L. & Kessel, M. FGF8 functions in the specification of the right body side of the chick. Curr. Biol. 9, 277–280 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Meyers, E. N. & Martin, G. R. Differences in left–right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285, 403–406 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Duester, G. Retinoic acid regulation of the somitogenesis clock. Birth Defects Res. C Embryo Today 81, 84–92 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Keegan, B. R., Feldman, J. L., Begemann, G., Ingham, P. W. & Yelon, D. Retinoic acid signaling restricts the cardiac progenitor pool. Science 307, 247–249 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Ryckebusch, L. et al. Retinoic acid deficiency alters second heart field formation. Proc. Natl Acad. Sci. USA 105, 2913–2918 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Collop, A. H. et al. Retinoic acid signaling is essential for formation of the heart tube in Xenopus. Dev. Biol. 291, 96–109 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hochgreb, T. et al. A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field. Development 130, 5363–5374 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Zile, M. H. et al. Retinoid signaling is required to complete the vertebrate cardiac left/right asymmetry pathway. Dev. Biol. 223, 323–338 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Buckingham, M., Meilhac, S. & Zaffran, S. Building the mammalian heart from two sources of myocardial cells. Nature Rev. Genet. 6, 826–835 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Cai, C. L. et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev. Cell 5, 877–889 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tickle, C. Making digit patterns in the vertebrate limb. Nature Rev. Mol. Cell Biol. 7, 45–53 (2006).

    Article  CAS  Google Scholar 

  91. McGlinn, E. & Tabin, C. J. Mechanistic insight into how Shh patterns the vertebrate limb. Curr. Opin. Genet. Dev. 16, 426–432 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Fernandez-Teran, M. et al. Role of dHAND in the anterior–posterior polarization of the limb bud: implications for the Sonic hedgehog pathway. Development 127, 2133–2142 (2000).

    CAS  PubMed  Google Scholar 

  93. Niederreither, K. et al. The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. Development 130, 2525–2534 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Wendling, O., Dennefeld, C., Chambon, P. & Mark, M. Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. Development 127, 1553–1562 (2000).

    CAS  PubMed  Google Scholar 

  95. Desai, T. J. et al. Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis. Dev. Biol. 291, 12–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Chen, F. et al. Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction. Development 134, 2969–2979 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. McCaffery, P., Zhang, J. & Crandall, J. E. Retinoic acid signaling and function in the adult hippocampus. J. Neurobiol. 66, 780–791 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Taupin, P. Adult neurogenesis in mammals. Curr. Opin. Mol. Ther. 8, 345–351 (2006).

    CAS  PubMed  Google Scholar 

  99. Guan, K., Chang, H., Rolletschek, A. & Wobus, A. M. Embryonic stem cell-derived neurogenesis. Retinoic acid induction and lineage selection of neuronal cells. Cell Tissue Res. 305, 171–176 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Bibel, M., Richter, J., Lacroix, E. & Barde, Y. A. Generation of a defined and uniform population of CNS progenitors and neurons from mouse embryonic stem cells. Nature Protoc. 2, 1034–1043 (2007).

    Article  CAS  Google Scholar 

  101. Lohnes, D. et al. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120, 2723–2748 (1994).

    CAS  PubMed  Google Scholar 

  102. Wendling, O., Ghyselinck, N. B., Chambon, P. & Mark, M. Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning. Development 128, 2031–2038 (2001).

    CAS  PubMed  Google Scholar 

  103. Merki, E. et al. Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proc. Natl Acad. Sci. USA 102, 18455–18460 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wong, L. F. et al. Retinoic acid receptor beta2 promotes functional regeneration of sensory axons in the spinal cord. Nature Neurosci. 9, 243–250 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Lepilina, A. et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127, 607–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Mollard, R. et al. Tissue-specific expression of retinoic acid receptor isoform transcripts in the mouse embryo. Mech. Dev. 94, 223–232 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Maden, M., Sonneveld, E., van der Saag, P. T. & Gale, E. The distribution of endogenous retinoic acid in the chick embryo: implications for developmental mechanisms. Development 125, 4133–4144 (1998).

    CAS  PubMed  Google Scholar 

  108. Mic, F. A., Molotkov, A., Benbrook, D. M. & Duester, G. Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis. Proc. Natl Acad. Sci. USA 100, 7135–7140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bastien, J. & Rochette-Egly, C. Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene 328, 1–16 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Rosenfeld, M. G., Lunyak, V. V. & Glass, C. K. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20, 1405–1428 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Balmer, J. E. & Blomhoff, R. Gene expression regulation by retinoic acid. J. Lipid Res. 43, 1773–1808 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Michalik, L. & Wahli, W. Guiding ligands to nuclear receptors. Cell 129, 649–651 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Bowles, J. & Koopman, P. Retinoic acid, meiosis and germ cell fate in mammals. Development 134, 3401–3411 (2007). This study, together with reference 116, showed that sex-specific regulation of RA catabolism by CYP26B1 is responsible for the differential timing of meiotic initiation in the male versus the female gonad.

    Article  CAS  PubMed  Google Scholar 

  114. Baltus, A. E. et al. In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nature Genet. 38, 1430–1434 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Bowles, J. et al. Retinoid signaling determines germ cell fate in mice. Science 312, 596–600 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Koubova, J. et al. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc. Natl Acad. Sci. USA 103, 2474–2479 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. MacLean, G., Li, H., Metzger, D., Chambon, P. & Petkovich, M. Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology 148, 4560–4567 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Vernet, N. et al. Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis. Endocrinology 147, 96–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Lufkin, T. et al. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc. Natl Acad. Sci. USA 90, 7225–7229 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ghyselinck, N. B. et al. Role of the retinoic acid receptor beta (RARbeta) during mouse development. Int. J. Dev. Biol. 41, 425–447 (1997).

    CAS  PubMed  Google Scholar 

  121. Luo, J., Sucov, H. M., Bader, J. A., Evans, R. M. & Giguere, V. Compound mutants for retinoic acid receptor (RAR) beta and RAR alpha 1 reveal developmental functions for multiple RAR beta isoforms. Mech. Dev. 55, 33–44 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Lohnes, D. et al. Function of retinoic acid receptor gamma in the mouse. Cell 73, 643–658 (1993).

    Article  CAS  PubMed  Google Scholar 

  123. Kastner, P. et al. Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78, 987–1003 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Sucov, H. M. et al. RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev. 8, 1007–1018 (1994).

    Article  CAS  PubMed  Google Scholar 

  125. Wendling, O., Chambon, P. & Mark, M. Retinoid X receptors are essential for early mouse development and placentogenesis. Proc. Natl Acad. Sci. USA 96, 547–551 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kastner, P. et al. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 10, 80–92 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Mendelsohn, C. et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120, 2749–2771 (1994).

    CAS  PubMed  Google Scholar 

  128. Dupe, V., Ghyselinck, N. B., Wendling, O., Chambon, P. & Mark, M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development 126, 5051–5059 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are indebted to P. Chambon for initiating much of the research described in this paper. Work in the authors' laboratories is supported by grants from the National Institutes of Health (R01 #HL070733) and American Heart Association (#0330265N) to K.N, and funding from the CNRS, INSERM, Université Louis Pasteur, and grants from the Agence Nationale pour la Recherche, Fondation pour la Recherche Médicale, and European Union (EVI-GENORET # LSHG-CT-2005-512036) to P.D.

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  1. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Karen Niederreither

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104 CNRS, U 596 INSERM, Université Louis Pasteur, BP 10142, Illkirch, F-67400, France

    Pascal Dollé

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Glossary

Morphogen

A substance that is active in pattern formation, the spatial concentration or activity of which varies and to which cells respond differently at different threshold concentrations.

Homeobox gene

(Hox gene). A member of the family of genes involved in patterning the animal body axis during development. In vertebrates, Hox genes are clustered together on defined chromosomes and their sequential expression (both over time and along the embryonic axis) is related to the position on the chromosome.

Neural tube

A cylindrical structure formed by dorsal midline closure of the neural plate (the embryonic neuroepithelium), and that will give rise to the brain and the spinal cord.

Mesoderm

One of the three embryonic germ layers that is generated during gastrulation. It is a mesenchymal cell population found between the embryonic ectoderm and endoderm, and its derivatives include the trunk skeleton, muscles, heart, dermis and various organ tissues.

Visceral endoderm

An extra-embryonic tissue — unrelated to the definitive endoderm lineage — that nourishes the vertebrate embryo.

Anophthalmia

Lack of eye development.

Primitive streak

A longitudinal cleft formed on the surface of the amniote early embryo by a convergence of cells. At the onset of gastrulation, epiblast cells migrate towards and into the streak, and consequently acquire a mesodermal cell fate.

Somites

Segmental structures, consisting of epithelial blocks of tissue surrounding a cavity called the somitocoele, which are formed sequentially in the paraxial (presomitic) mesoderm and give rise to the sclerotome (precursors of the axial skeleton) and dermomyotome (precursors of the dermis of the back and skeletal muscles).

Morpholino

Chemically modified, antisense oligonucleotides that are mainly used in zebrafish and X. laevis to inhibit either the translation or splicing of mRNAs.

Cytochrome p450

A member of the large family of haem-containing enzymes, usually acting as monooxygenases and involved in the metabolism of many endogenous and exogenous compounds, as well as in hormone biosynthesis and breakdown.

Glaucoma

Pathological condition resulting from abnormally elevated pressure in the liquid that fills the anterior chamber of the eye (the aqueous humour).

Teratogenic

A molecule that causes malformation of an embryo.

Rhombomeres

Segmental units transiently found in the hindbrain neuroepithelium, that adopt distinct molecular and cellular properties, restrictions in cell mixing, and ordered domains of gene expression.

Neurectoderm

Region of the definitive embryonic ectoderm that undergoes neural induction and forms a columnar neuroepithelium or neural plate.

Mesenchyme

Describes populations of cells that are not part of an epithelial sheet. In the early embryo, most (although not all) mesenchymal cell populations are derived from the mesoderm.

Gastrula

Vertebrate embryo at the gastrulation stage.

Neurula

Vertebrate embryo at the neurulation (formation of the neural plate) stage.

Frontonasal

Describes the anteriormost region of the embryonic face, in which nasal and ocular structures will develop.

Axial mesendoderm

Midline embryonic cells prior to the segregation of mesoderm and definitive endoderm, these cells will give rise to the notochord and floor plate of the neural tube, and produce several molecules involved in neural induction or patterning, including SHH.

Telencephalon

Rostral (anterior) region of the forebrain, which gives rise to most of the cerebral hemispheres, including the cerebral cortex.

Optic vesicle

Evagination of the forebrain neuroectoderm, from which both the neural and pigmented layers or the retina will develop.

Cardiac crescent

Paired, crescent-like cell populations in the anterior lateral mesoderm, which later fuse along the midline to form the embryonic heart tube.

Sertoli cells

Columnar, somatic cells of the testis seminiferous epithelium, which are responsive to FSH (follicle-stimulating hormone; a pituitary hormone) and in turn produce various hormones and proteins, including glial cell derived neurotrophic factor (GDNF).

Mesonephros

The mid-region of the embryonic kidney that arises within the intermediate mesoderm between the pronephros and the metanephros (the definitive kidney). The gonad develops on the medial surface of this transient tissue, which also contains the primordia for the male (mesonephric) and female (paramesonephric or Müllerian) sex ducts.

Seminiferous tubules

Coiled tubes within the testis, containing an epithelium composed of somatic Sertoli cells and germ cells at various stages of differentiation.

Spina bifida

A congenital malformation that is due to a lack of closure of the caudal region of the neural tube, resulting in a protrusion of the lumbosacral spinal cord outside of the body.

Branchial arches

Also known as pharyngeal arches. A series of paired segmental structures that are positioned on either side of the developing pharynx and are composed of ectoderm, mesoderm and neural crest cells. In mammals, the branchial arches contribute to pharyngeal organs and to the connective, skeletal, neural and vascular tissues of the head and neck.

Subventricular zone

A neurogenic region that lines the ventricles of the adult brain.

Olfactory bulb

Rostralmost portion of the mammalian brain, which receives inputs from the sensory olfactory axons.

Hippocampus

A neurogenic region of the forebrain that has important functions in learning and memory.

Embryoid bodies

Cell aggregates formed when embryonic stem cells are grown in suspension culture, and in which various cell types can be induced according to the culture conditions.

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Niederreither, K., Dollé, P. Retinoic acid in development: towards an integrated view. Nat Rev Genet 9, 541–553 (2008). https://doi.org/10.1038/nrg2340

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