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: 3.55). 11/2008; 325(1):60-70. DOI: 10.1016/j.ydbio.2008.09.022
Source: PubMed


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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Available from: Joshua S Waxman, Sep 29, 2015
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    • "mineralization of the opercular, ceratohyal and vertebrae are reported in zebrafish (Danio rerio) mutants lacking RA degradation (Laue et al., 2008). A recent study employing systematic knockdown of RARs in zebrafish reveals the major receptors involved in pharyngeal and pectoral fin skeletogenesis (Linville et al., 2009). Except for RARs, changes of RXR expression are found in European seabass (Dicentrarchus labrax) with disturbed bone formation in the cephalic region and vertebral deformities induced by the feeding on excessive highly unsaturated fatty acid (Villeneuve et al., 2006). "
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    ABSTRACT: Tributyltin (TBT) is a ubiquitous marine environmental contaminant, which has been known to cause axial skeletal deformities in fish embryos. However, the effects of TBT on the craniofacial cartilage development of fishes remain unclear. The present study was designed to investigate the effects of waterborne TBT at environmental levels (0, 0.1, 1, and 10 ng L(-1) as Sn) on craniofacial cartilage development in embryos of the rockfish (Sebastiscus marmoratus). Our study showed that TBT exposure induced craniofacial skeletal deformities, such as reduction of the craniofacial skeleton elements and a shorter lower jaw. The expressions of retinoic acid receptor α, sonic hedgehog, and proliferating cell nuclear antigen were depressed and the expressions of vitamin D receptor were increased in the rockfish embryos after TBT exposure. In addition, the activities of Ca(2+)-ATPase were inhibited after TBT exposure. These results suggested that TBT might perturb the proliferation and differentiation of chondrocytes, and disturb calcium homeostasis, thus disorganizing craniofacial skeletal development.
    Marine environmental research 01/2012; 77:6-11. DOI:10.1016/j.marenvres.2011.12.008 · 2.76 Impact Factor
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    • "As such, vgll2a could also be acting as an effector of FGF and/ or RA signaling in the regulation of cell death. FGF and RA signaling have also been shown to regulate endodermal pouch morphogenesis (Crump et al., 2004; Kopinke et al., 2006; Linville et al., 2009). We first observe vgll2a expression in the pharyngeal endoderm in a subset of cells as they began to evaginate to form the first endodermal pouch and its expression in the pharyngeal endoderm persists throughout pouch morphogenesis. "
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    ABSTRACT: Invertebrate and vertebrate vestigial (vg) and vestigial-like (VGLL) genes are involved in embryonic patterning and cell fate determination. These genes encode cofactors that interact with members of the Scalloped/TEAD family of transcription factors and modulate their activity. We have previously shown that, in mice, Vgll2 is differentially expressed in the developing facial prominences. In this study, we show that the zebrafish ortholog vgll2a is expressed in the pharyngeal endoderm and ectoderm surrounding the neural crest derived mesenchyme of the pharyngeal arches. Moreover, both the FGF and retinoic acid (RA) signaling pathways, which are critical components of the hierarchy controlling craniofacial patterning, regulate this domain of vgll2a expression. Consistent with these observations, vgll2a is required within the pharyngeal endoderm for NCC survival and pharyngeal cartilage development. Specifically, knockdown of Vgll2a in zebrafish embryos using Morpholino injection results in increased cell death within the pharyngeal arches, aberrant endodermal pouch morphogenesis, and hypoplastic cranial cartilages. Overall, our data reveal a novel non-cell autonomous role for Vgll2a in development of the NCC-derived vertebrate craniofacial skeleton.
    Developmental Biology 09/2011; 357(1):269-81. DOI:10.1016/j.ydbio.2011.06.034 · 3.55 Impact Factor
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    • "To gain further insight into the roles of endogenous RA signaling, and to test the hypothesis that RARαb mediates the effects of endogenous RA signaling on photoreceptors, a morpholino oligonucleotide against the RAR subtype RARαb [60] was injected into one-cell stage embryos carrying RARE-YFP. In all of these experiments we co-injected an antisense morpholino against p53, in order to suppress MO-related cell death [54,60]. Embryos injected with the rarαb/p53 MO combination will be referred to as RARαb morphants. "
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    ABSTRACT: Retinoic acid (RA) is important for vertebrate eye morphogenesis and is a regulator of photoreceptor development in the retina. In the zebrafish, RA treatment of postmitotic photoreceptor precursors has been shown to promote the differentiation of rods and red-sensitive cones while inhibiting the differentiation of blue- and UV-sensitive cones. The roles played by RA and its receptors in modifying photoreceptor fate remain to be determined. Treatment of zebrafish embryos with RA, beginning at the time of retinal progenitor cell proliferation and prior to photoreceptor terminal mitosis, resulted in a significant alteration of rod and cone mosaic patterns, suggesting an increase in the production of rods at the expense of red cones. Quantitative pattern analyses documented increased density of rod photoreceptors and reduced local spacing between rod cells, suggesting rods were appearing in locations normally occupied by cone photoreceptors. Cone densities were correspondingly reduced and cone photoreceptor mosaics displayed expanded and less regular spacing. These results were consistent with replacement of approximately 25% of positions normally occupied by red-sensitive cones, with additional rods. Analysis of embryos from a RA-signaling reporter line determined that multiple retinal cell types, including mitotic cells and differentiating rods and cones, are capable of directly responding to RA. The RA receptors RXRγ and RARαb are expressed in patterns consistent with mediating the effects of RA on photoreceptors. Selective knockdown of RARαb expression resulted in a reduction in endogenous RA signaling in the retina. Knockdown of RARαb also caused a reduced production of rods that was not restored by simultaneous treatments with RA. These data suggest that developing retinal cells have a dynamic sensitivity to RA during retinal neurogenesis. In zebrafish RA may influence the rod vs. cone cell fate decision. The RARαb receptor mediates the effects of endogenous, as well as exogenous RA, on rod development.
    BMC Developmental Biology 08/2011; 11(1):51. DOI:10.1186/1471-213X-11-51 · 2.67 Impact Factor
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