Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

Retinoic acid (RA) is essential for normal vertebrate development, including the patterning of the central nervous system. During early embryogenesis, RA is produced in the trunk mesoderm through the metabolism of vitamin A derived from the maternal diet and behaves as a morphogen in the developing hindbrain where it specifies nested domains of Hox gene expression. The loss of endogenous sources of RA can be rescued by treatment with a uniform concentration of exogenous RA, indicating that domains of RA responsiveness can be shaped by mechanisms other than the simple diffusion of RA from a localized posterior source. Here, we show that the cytochrome p450 enzymes of the Cyp26 class, which metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development. In zebrafish embryos depleted of the orthologs of the three mammalian CYP26 genes CYP26A1, CYP26B1 and CYP26C1, the entire hindbrain expresses RA-responsive genes that are normally restricted to nested domains in the posterior hindbrain. Furthermore, we show that Cyp26 enzymes are essential for exogenous RA to rescue hindbrain patterning in RA-depleted embryos. We present a `gradient-free' model for hindbrain patterning in which differential RA responsiveness along the hindbrain anterior-posterior axis is shaped primarily by the dynamic expression of RA-degrading enzymes.

[1]  上原 雅行 CYP26A1 and CYP26C1 cooperatively regulate anterior-posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse , 2007 .

[2]  P. Chambon,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. , 2007, Developmental biology.

[3]  P. Purushottamachar,et al.  Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases. , 2006, Bioorganic & medicinal chemistry.

[4]  J. Postlethwait,et al.  Characterization of retinoid-X receptor genes rxra, rxrba, rxrbb and rxrg during zebrafish development. , 2006, Gene expression patterns : GEP.

[5]  J. Postlethwait,et al.  Characterization of the retinoic acid receptor genes raraa, rarab and rarg during zebrafish development. , 2006, Gene expression patterns : GEP.

[6]  D. Wotton,et al.  TGIF Inhibits Retinoid Signaling , 2006, Molecular and Cellular Biology.

[7]  C. Kimmel,et al.  Dynamic and sequential patterning of the zebrafish posterior hindbrain by retinoic acid. , 2005, Developmental biology.

[8]  M. Maden,et al.  The control of morphogen signalling: regulation of the synthesis and catabolism of retinoic acid in the developing embryo. , 2005, Developmental biology.

[9]  John H Postlethwait,et al.  The zebrafish gene map defines ancestral vertebrate chromosomes. , 2005, Genome research.

[10]  Qingshun Zhao,et al.  Molecular cloning and expression of a novel CYP26 gene (cyp26d1) during zebrafish early development. , 2005, Gene expression patterns : GEP.

[11]  L. Gresh,et al.  Shifting boundaries of retinoic acid activity control hindbrain segmental gene expression , 2005, Development.

[12]  Á. Raya,et al.  Retinoic acid signalling links left–right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo , 2005, Nature.

[13]  Wendy A Bickmore,et al.  Nuclear re-organisation of the Hoxb complex during mouse embryonic development , 2005, Development.

[14]  H. Okamoto,et al.  Retinoic acid-metabolizing enzyme Cyp26a1 is essential for determining territories of hindbrain and spinal cord in zebrafish. , 2005, Developmental biology.

[15]  E. Linney,et al.  Expression of cyp26b1 during zebrafish early development. , 2005, Gene expression patterns : GEP.

[16]  C. Moens,et al.  vhnf1 integrates global RA patterning and local FGF signals to direct posterior hindbrain development in zebrafish , 2004, Development.

[17]  A. Meyer,et al.  Beyond the neckless phenotype: influence of reduced retinoic acid signaling on motor neuron development in the zebrafish hindbrain. , 2004, Developmental biology.

[18]  F. Rosa,et al.  The zebrafish Iroquois gene iro7 positions the r4/r5 boundary and controls neurogenesis in the rostral hindbrain , 2004, Development.

[19]  M. Maden,et al.  Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[20]  E. Linney,et al.  Feedback mechanisms regulate retinoic acid production and degradation in the zebrafish embryo , 2004, Mechanisms of Development.

[21]  J. Bastien,et al.  Nuclear retinoid receptors and the transcription of retinoid-target genes. , 2004, Gene.

[22]  Y. Saijoh,et al.  Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. , 2004, Developmental cell.

[23]  M. Taimi,et al.  A Novel Human Cytochrome P450, CYP26C1, Involved in Metabolism of 9-cis and All-trans Isomers of Retinoic Acid* , 2004, Journal of Biological Chemistry.

[24]  R. Lovell-Badge,et al.  dead end, a Novel Vertebrate Germ Plasm Component, Is Required for Zebrafish Primordial Germ Cell Migration and Survival , 2003, Current Biology.

[25]  P. Dollé,et al.  Cyp26C1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development. , 2003, Gene expression patterns : GEP.

[26]  W. Driever,et al.  Provitamin A conversion to retinal via theβ ,β-carotene-15,15′-oxygenase (bcox) is essential for pattern formation and differentiation during zebrafish embryogenesis , 2003, Development.

[27]  A. Amores,et al.  The role of a retinoic acid response element in establishing the anterior neural expression border of Hoxd4 transgenes , 2003, Mechanisms of Development.

[28]  Stephen W. Wilson,et al.  Distinct roles for Fgf, Wnt and retinoic acid in posteriorizing the neural ectoderm. , 2002, Development.

[29]  M. Flexor,et al.  Activation of Retinoic Acid Receptor-dependent Transcription by All-trans-retinoic Acid Metabolites and Isomers* , 2002, The Journal of Biological Chemistry.

[30]  Stephen W. Wilson,et al.  Retinoic acid signalling in the zebrafish embryo is necessary during pre-segmentation stages to pattern the anterior-posterior axis of the CNS and to induce a pectoral fin bud. , 2002, Development.

[31]  V. Njar Cytochrome p450 retinoic acid 4-hydroxylase inhibitors: potential agents for cancer therapy. , 2002, Mini reviews in medicinal chemistry.

[32]  V. Prince,et al.  Constructing the hindbrain: Insights from the zebrafish , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[33]  R. Haselbeck,et al.  Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. , 2002, Development.

[34]  P. Chambon,et al.  Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development , 2002, Nature Genetics.

[35]  A. Gavalas ArRAnging the hindbrain , 2002, Trends in Neurosciences.

[36]  P. Chambon,et al.  Differential expression of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during murine organogenesis , 2002, Mechanisms of Development.

[37]  A. Waskiewicz,et al.  Zebrafish Meis functions to stabilize Pbx proteins and regulate hindbrain patterning. , 2001, Development.

[38]  P. Chambon,et al.  Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development , 2001, Mechanisms of Development.

[39]  K. Umesono,et al.  Active repression of RAR signaling is required for head formation. , 2001, Genes & development.

[40]  P. Ingham,et al.  The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain. , 2001, Development.

[41]  V. Dupé,et al.  Hindbrain patterning involves graded responses to retinoic acid signalling. , 2001, Development.

[42]  P. Chambon,et al.  The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. , 2001, Genes & development.

[43]  J. Rossant,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. , 2001, Genes & development.

[44]  Winifred Armstrong,et al.  Marrying Planning, Economics and Environment: Is South Africa ahead of the curve? , 2000 .

[45]  M. Petkovich,et al.  Cytochrome P450RAI(CYP26) promoter: a distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism. , 2000, Molecular endocrinology.

[46]  M. Featherstone,et al.  Murine Hoxd4 expression in the CNS requires multiple elements including a retinoic acid response element , 2000, Mechanisms of Development.

[47]  L. Dillen,et al.  R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents. , 2000, The Journal of pharmacology and experimental therapeutics.

[48]  P. Chambon,et al.  Retinoic acid synthesis and hindbrain patterning in the mouse embryo. , 2000, Development.

[49]  G. Eichele,et al.  Complementary domains of retinoic acid production and degradation in the early chick embryo. , 1999, Developmental biology.

[50]  M. Zile,et al.  Hindbrain respecification in the retinoid-deficient quail , 1999, Mechanisms of Development.

[51]  D. Nelson,et al.  A second CYP26 P450 in humans and zebrafish: CYP26B1. , 1999, Archives of biochemistry and biophysics.

[52]  P. Chambon,et al.  Embryonic retinoic acid synthesis is essential for early mouse post-implantation development , 1999, Nature Genetics.

[53]  R. Krumlauf,et al.  Initiation of Rhombomeric Hoxb4 Expression Requires Induction by Somites and a Retinoid Pathway , 1998, Neuron.

[54]  R. Ho,et al.  Zebrafish hox genes: expression in the hindbrain region of wild-type and mutants of the segmentation gene, valentino. , 1998, Development.

[55]  G. Barsh,et al.  Equivalence in the genetic control of hindbrain segmentation in fish and mouse. , 1998, Development.

[56]  Y. Fujii‐Kuriyama,et al.  Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos , 1997, The EMBO journal.

[57]  F. Dilworth,et al.  Identification of the Retinoic Acid-inducible All-trans-retinoic Acid 4-Hydroxylase* , 1996, The Journal of Biological Chemistry.

[58]  I. Kostetskii,et al.  Vitamin A-deficient quail embryos have half a hindbrain and other neural defects , 1996, Current Biology.

[59]  J. Zeitlinger,et al.  Endogenous retinoids in the zebrafish embryo and adult , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[60]  C. Kimmel,et al.  Stages of embryonic development of the zebrafish , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[61]  R. Krumlauf,et al.  Role of a conserved retinoic acid response element in rhombomere restriction of Hoxb-1. , 1994, Science.

[62]  S. Brenner,et al.  A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1 , 1994, Nature.

[63]  G. Folkers,et al.  The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification , 1993, Nature.

[64]  M. Shago,et al.  Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. , 1991, Genes & development.

[65]  A. Simeone,et al.  Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells , 1990, Nature.

[66]  A. Lumsden The cellular basis of segmentation in the developing hindbrain , 1990, Trends in Neurosciences.

[67]  J. Russo,et al.  Inhibition of mouse cytosolic aldehyde dehydrogenase by 4-(diethylamino)benzaldehyde. , 1988, Biochemical pharmacology.

[68]  F. Rosa,et al.  Summary The zebrafish Iroquois gene iro 7 positions the r 4 / r 5 boundary and controls neurogenesis in the rostral hindbrain , 2022 .