PUBLICATION

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

Authors

Hernandez, R.E., Putzke, A.P., Myers, J.P., Margaretha, L., and Moens, C.B.

ID

ZDB-PUB-061227-41

Date

2007

Source

Development (Cambridge, England) 134(1): 177-187 (Journal)

Registered Authors

Hernandez, Rafael, Moens, Cecilia, Myers, Jonathan, Putzke, Aaron

Keywords

Retinoic acid, Hindbrain, Cyp26, Hox, Morphogen, Zebrafish

MeSH Terms

Cytochrome P-450 Enzyme System/genetics
Cytochrome P-450 Enzyme System/metabolism*
Tretinoin/metabolism*
Tretinoin/pharmacology
Body Patterning/physiology*
In Situ Hybridization
Animals
Rhombencephalon/drug effects
Rhombencephalon/embryology*
Rhombencephalon/metabolism
Gene Expression Regulation, Developmental/drug effects
Embryo, Nonmammalian
Models, Biological
Oligonucleotides, Antisense/pharmacology
Organogenesis
Embryonic Development/drug effects*
Genes, Homeobox
Zebrafish/embryology
Zebrafish/genetics
Zebrafish/metabolism

(all 20)

PubMed

17164423 Full text @ Development

CTD

17164423

Abstract

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.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
aldh1a2	WT	standard conditions	Bud		mesoderm	ISH	Fig. 1
aldh1a2	WT	standard conditions	1-4 somites		mesoderm	ISH	Fig. 1
aldh1a2	WT	standard conditions	75%-epiboly		neuroectoderm	ISH	Fig. 1
cyp26a1	WT	standard conditions	75%-epiboly		margin	ISH	Fig. 1
cyp26a1	WT	standard conditions	75%-epiboly		neuroectoderm	ISH	Fig. 1
cyp26a1	WT	standard conditions	Bud		neuroectoderm	ISH	Fig. 1
cyp26a1	WT	standard conditions	1-4 somites		neuroectoderm	ISH	Fig. 1
cyp26a1	WT	standard conditions	1-4 somites		tail bud	ISH	Fig. 1
cyp26a1	WT	standard conditions	Bud		tail bud	ISH	Fig. 1
cyp26b1	cyp26a1^rw716/rw716	chemical treatment: all-trans-retinoic acid	5-9 somites	Not Detected	neural rod	ISH	Fig. 5

1 - 10 of 206

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1	standard conditions	14-19 somites	hindbrain wholly posteriorized, abnormal	Fig. S4
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1	standard conditions	14-19 somites	hindbrain wholly posteriorized, abnormal	Fig. 2
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1	standard conditions	14-19 somites	pharyngeal endoderm condensed, abnormal	Fig. 2
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1	standard conditions	14-19 somites	rhombomere 4 increased size, abnormal	Fig. S4
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1	standard conditions	14-19 somites	rhombomere 4 increased size, abnormal	Fig. 2
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1	standard conditions	14-19 somites	vagal lobe distended, abnormal	Fig. 2
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-dnd1	standard conditions	14-19 somites	rhombomere 4 increased size, abnormal	Fig. S4
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-dnd1	standard conditions	14-19 somites	rhombomere 4 increased size, abnormal	Fig. 2
cyp26a1^rw716/rw716 + MO1-cyp26c1 + MO1-dnd1	standard conditions	14-19 somites	hindbrain morphology, abnormal	Fig. 2
cyp26a1^rw716/rw716 + MO1-cyp26c1 + MO1-dnd1	standard conditions	14-19 somites	hindbrain wholly posteriorized, abnormal	Fig. S4

1 - 10 of 13

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
rw716		Point Mutation	cyp26a1

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
cyp26b1	MO1-cyp26b1	MRPHLNO
cyp26b1	MO2-cyp26b1	MRPHLNO
cyp26c1	MO1-cyp26c1	MRPHLNO
cyp26c1	MO2-cyp26c1	MRPHLNO
dnd1	MO1-dnd1	MRPHLNO

Fish

Fish
cyp26a1^rw716/rw716
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-cyp26c1
cyp26a1^rw716/rw716 + MO1-cyp26b1 + MO1-dnd1
cyp26a1^rw716/rw716 + MO1-cyp26c1 + MO1-dnd1
cyp26a1^rw716/rw716 + MO1-dnd1
WT

1 - 6 of 6

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Antibodies

Orthology

Gene	Orthology
cyp26a1
cyp26c1

Engineered Foreign Genes

Mapping

Hernandez et al., 2007 ZDB-PUB-061227-41 PMID:17164423

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

Hernandez et al., 2007

ZDB-PUB-061227-41
PMID:17164423