Provitamin A conversion to retinal via theβ,β-carotene-15,15′-oxygenase (<i>bcox</i>) is essential for pattern formation and differentiation during zebrafish embryogenesis

Lampert, Johanna M.; Holzschuh, Jochen; Hessel, Susanne; Driever, Wolfgang; Vogt, Klaus; Lintig, Johannes von

doi:10.1242/dev.00437

Cited by 132 publications

(129 citation statements)

References 69 publications

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“…The presence of severe ventral retinal defects and the absence of cellular differentiation in apc mutant embryos were highly reminiscent of retinoid deficiency (14,15,17,18,25). This finding, coupled with our previous findings that apc regulates RA production in the intestine, led us to hypothesize that retinoid deficiency underlies the defects present in apc mutant retinas.…”

Section: Resultsmentioning

confidence: 65%

“…The ventral retina, in particular, is highly dependent on RA. For example, Hyatt et al (17) demonstrated that zebrafish treated with exogenous RA displayed an enhancement of ventral retina characteristics, whereas knockdown of an enzyme involved in RA biosynthesis (bcox) hindered the establishment of the ventral retina (18). In addition, recent studies show that targeted deletion of the retinoid receptor RXR␣ within the mouse retinal pigmented epithelium (RPE) caused RPE abnormalities, including the appearance of congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium-like lesions similar to those present in mice bearing mutated APC (19,20).…”

mentioning

confidence: 99%

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Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Nadauld

Chidester

Shelton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium is an ocular lesion found in patients harboring mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. We report that Apc-deficient zebrafish display developmental abnormalities of both the lens and retina. Injection of dominantnegative Lef reduced Wnt signaling in the lens but did not rescue retinal differentiation defects. In contrast, treatment of apc mutants with all-trans retinoic acid rescued retinal differentiation defects but had no apparent effect on the lens. We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC. Morpholino knockdown of Rdh5 phenocopied the apc mutant retinal differentiation defects and was rescued by treatment with exogenous all-trans retinoic acid. Microarray analyses of apc mutants and Rdh5 morphants revealed a profound overlap in the transcriptional profile of these embryos. These findings support a model wherein Apc serves a dual role in regulating Wnt and retinoic acid signaling within the eye and suggest retinoic acid deficiency as an explanation for APC mutation-associated retinal defects such as congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium.colon cancer ͉ retina ͉ APC

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Section: Resultsmentioning

confidence: 65%

mentioning

confidence: 99%

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Nadauld

Chidester

Shelton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…8). Stores of RA are deposited maternally into the yolk, as are stores of dietary vitamin A, the precursor of RA (24,25). These stores vary between embryos because the amount of vitamin A present in the maternal diet fluctuates, and the rate of deposition into the yolk varies, as has been shown for numerous bird species (e.g., ref.…”

Section: Discussionmentioning

confidence: 89%

Cyp26 enzymes function in endoderm to regulate pancreatic field size

Kinkel¹,

Sefton²,

Kikuchi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The control of organ size and position relies, at least in part, upon appropriate regulation of the signals that specify organ progenitor fields. Pancreatic cell fates are specified by retinoic acid (RA), and proper size and localization of the pancreatic field are dependent on tight control of RA signaling. Here we show that the RAdegrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field. Disruption of Cyp26 function causes a dramatic expansion of pancreatic cell types toward the anterior of the embryo. The cyp26a1 gene is expressed in the anterior trunk endoderm at developmental stages when RA is signaling to specify pancreas, and analysis of cyp26a1/giraffe (gir) mutant zebrafish embryos confirms that cyp26a1 plays the primary role in setting the anterior limit of the pancreas. Analysis of the gir mutants further reveals that cyp26b1 and cyp26c1 function redundantly to partially compensate for loss of Cyp26a1 function. We used cell transplantation to determine that Cyp26a1 functions directly in endoderm to modulate RA signaling and limit the pancreatic field. Taken together with our finding that endodermal expression of cyp26 genes is subject to positive regulation by RA, our data reveal a feedback loop within the endoderm. Such feedback can maintain consistent levels of RA signaling, despite environmental fluctuations in RA concentration, thus ensuring a consistent size and location of the pancreatic field.␤-cell ͉ insulin ͉ retinoic acid ͉ zebrafish

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“…Maternally-derived RA is present at very low levels in zebrafish eggs and early embryos prior to the onset of embryonic RA synthesis, and is therefore unlikely to be a teratogenic risk (Costaridis et al, 1996). However, the levels of maternally loaded retinal -the immediate precursor of RA -are higher (9 pmol/egg) (Costaridis et al, 1996;Lampert et al, 2003). We asked whether Cyp26a1 protects against teratogenicity of RA precursors.…”

Section: Research Article Cyp26 Enzymes In Hindbrain Developmentmentioning

confidence: 99%

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

et al. 2007

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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.

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Provitamin A conversion to retinal via theβ,β-carotene-15,15′-oxygenase (bcox) is essential for pattern formation and differentiation during zebrafish embryogenesis

Cited by 132 publications

References 69 publications

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Cyp26 enzymes function in endoderm to regulate pancreatic field size

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

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