Combinatorial roles for zebrafish retinoic acid receptors in the hindbrain, limbs and pharyngeal arches.

Department of Developmental and Cell Biology, Developmental Biology Center, University of California, Irvine, CA 92697, USA.
Developmental Biology (Impact Factor: 3.64). 11/2008; 325(1):60-70. DOI: 10.1016/j.ydbio.2008.09.022
Source: PubMed

ABSTRACT Retinoic acid (RA) signaling regulates multiple aspects of vertebrate embryonic development and tissue patterning, in part through the local availability of nuclear hormone receptors called retinoic acid receptors (RARs) and retinoid receptors (RXRs). RAR/RXR heterodimers transduce the RA signal, and loss-of-function studies in mice have demonstrated requirements for distinct receptor combinations at different stages of embryogenesis. However, the tissue-specific functions of each receptor and their individual contributions to RA signaling in vivo are only partially understood. Here we use morpholino oligonucleotides to deplete the four known zebrafish RARs (raraa, rarab, rarga, and rargb). We show that while all four are required for anterior-posterior patterning of rhombomeres in the hindbrain, there are unique requirements for rarga in the cranial mesoderm for hindbrain patterning, and rarab in lateral plate mesoderm for specification of the pectoral fins. In addition, the alpha subclass (raraa, rarab) is RA inducible, and of these only raraa expression is RA-dependent, suggesting that these receptors establish a region of particularly high RA signaling through positive-feedback. These studies reveal novel tissue-specific roles for RARs in controlling the competence and sensitivity of cells to respond to RA.

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    ABSTRACT: Retinoic acid (RA) signalling is important to normal development. However, the function of the different retinoic acid receptors (RAR), RARα, RARβ and RARγ is as yet unclear. We have used wild type and transgenic zebrafish to examine the role of RARγ. Treatment of zebrafish embryos with an RARγ-specific agonist reduced somite formation and axial length, which was associated with a loss of hoxb 13a expression and less clear alterations in hoxc 11a or myoD expression. Treatment with the RARγ agonist also disrupted formation of tissues arising from cranial neural crest, including cranial bones and anterior neural ganglia. There was a loss of Sox 9-immunopositive neural crest stem/progenitor cells in the same anterior regions. Pectoral fin outgrowth was blocked by RARγ agonist treatment. However, there was no loss of Tbx-5-immunopositive lateral plate mesodermal stem/progenitor cells and the block was reversed by agonist wash out or by co-treatment with an RARγ antagonist. Regeneration of the caudal fin was also blocked by RARγ agonist treatment, which associated with a loss of canonical Wnt signalling. This regenerative response was restored by agonist wash out or co-treatment with the RARγ antagonist. These findings suggest that RARγ plays an essential role in maintaining stem/progenitor cells during embryonic development and tissue regeneration when the receptor is in its non-ligated state.
    Stem Cells and Development 09/2014; DOI:10.1089/scd.2014.0235 · 4.20 Impact Factor
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    ABSTRACT: Retinoic Acid (RA), the main active vitamin A derivative, is crucial for embryo development, regulating cellular processes, embryo patterning and organogenesis. Many studies performed in mammalian or avian models have successfully undertaken the investigation of the role played by RA during embryogenesis. However, since the early 1980's, the zebrafish (Daniorerio) has emerged as a powerful developmental model to study the in vivo role of RA during embryogenesis. Unlike other vertebrate models, zebrafish embryogenesis is external, allowing the observation of the translucent embryo from the earliest steps, but also providing an easily accessible system for pharmacological treatment or genetic approaches. Therefore, zebrafish research largely participates in deciphering the role of RA during development and this review aims at illustrating different concepts of RA signalling based on the research performed on zebrafish. Indeed, RA action relies on a multitude of cross-talkwith other signalling pathways and requires a coordinated, dynamic and fine-regulation of its level and activity in both temporal and spatial dimensions. This review also highlights major advances that have been discovered using zebrafish such as the observation of the RA gradient in vivofor the first time, the effects of RA signalling in brain patterning, its role in establishing left right asymmetry and its effects on the development of a variety of organs and tissues including the heart, blood, bone and fat. This review demonstrates that the zebrafish is a convenient and powerful model to study retinoic acid signalling during vertebrate embryogenesis. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 06/2014; 1849(2). DOI:10.1016/j.bbagrm.2014.05.030 · 5.44 Impact Factor
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    ABSTRACT: During development of the zebrafish inner ear, regional patterning in the ventral half of the otic vesicle establishes zones of gene expression that correspond to neurogenic, sensory and non-neural cell fates. FGF and Retinoic acid (RA) signalling from surrounding tissues are known to have an early role in otic placode induction and otic axial patterning, but how external signalling cues are translated into intrinsic patterning during otic vesicle (OV) stages is not yet understood. FGF and RA signalling pathway members are expressed in and around the OV, suggesting important roles in later patterning or maintenance events. We have analysed the temporal requirement of FGF and RA signalling for otic development at stages after initial anteroposterior patterning has occurred. We show that high level FGF signalling acts to restrict sensory fates, whereas low levels favour sensory hair cell development; in addition, FGF is both required and sufficient to promote the expression of the non-neural marker otx1b in the OV. RA signalling has opposite roles: it promotes sensory fates, and restricts otx1b expression and the development of non-neural fates. This is surprisingly different from the earlier requirement for RA signalling in specification of non-neural fates via tbx1 expression, and highlights the shift in regulation that takes place between otic placode and vesicle stages in zebrafish. Both FGF and RA signalling are required for the development of the otic neurogenic domain and the generation of otic neuroblasts. In addition, our results indicate that FGF and RA signalling act in a feedback loop in the anterior OV, crucial for pattern refinement.
    PLoS Genetics 12/2014; 10(12):e1004858. DOI:10.1371/journal.pgen.1004858 · 8.17 Impact Factor


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