Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038379 (strabismus)
 9,317 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Dapper/Frodo family of proteins are Dishevelled-interacting regulators of Wnt signaling. In this study, I characterize the regulation of the early expression patterns of dpr1 and dpr2. Although both dpr1 and dpr2 are expressed on the prospective dorsal side, I find that their pregastrula expression patterns have differences that have not been reported previously. Early dpr1 expression is much more dynamic than dpr2 expression. I use gain and loss of function experiments to identify dorsal organizer genes that regulate dpr1 and dpr2 expression. The dorsalizing factors beta-catenin, Bozozok (Boz), Noggin (Nog), and the mesendoderm-inducing factor Squint (Sqt) are all able to induce ectopic expression of dpr1 and dpr2. In reciprocal loss of function experiments, loss of maternal beta-catenin signaling leads to loss of early dorsal dpr1 and dpr2 expression, whereas loss of Boz and/or Nodal signaling does not. Ectopic expression of the ventralizing molecule Bmp2b leads to reduction of dpr1 and dpr2 expression. These results suggest that, in early zebrafish development, dpr1 and dpr2 are targets of beta-catenin and/or an unknown downstream effector. Their expression from 30% epiboly through shield is maintained by Nodal signaling and likely refined by the mutually antagonistic effects of Boz and bone morphogenetic protein signaling.
 ...
PMID:Regulation of the early expression patterns of the zebrafish Dishevelled-interacting proteins Dapper1 and Dapper2. 1576 13

We have used the maternal effect mutant ichabod, which is deficient in maternal beta-catenin signaling, to test for the epistatic relationship between beta-catenin activation, FGF signaling and bozozok, squint and chordin expression. Injection of beta-catenin RNA into ichabod embryos can completely rescue normal development. By contrast, when FGF signaling is inhibited, beta-catenin did not induce goosecoid and chordin, repress bmp4 expression or induce a dorsal axis. These results demonstrate that FGF signaling is necessary for beta-catenin induction of the zebrafish organizer. We show that FGFs function downstream of squint and bozozok to turn on chordin expression. Full rescue of ichabod by Squint is dependent on FGF signaling, and partial rescue by FGFs is completely dependent on chordin. By contrast, Bozozok can rescue the complete anteroposterior axis, but not notochord, in embryos blocked in FGF signaling. Surprisingly, accumulation of bozozok transcript in beta-catenin RNA-injected ichabod embryos is also dependent on FGF signaling, indicating a role of FGFs in maintenance of bozozok RNA. These experiments show that FGF-dependent organizer function operates through both bozozok RNA accumulation and a pathway consisting of beta-catenin-->Squint-->FGF-->Chordin, in which each component is sufficient for expression of the downstream factors of the pathway, and in which Nodal signaling is required for FGF gene expression and FGF signaling is required for Squint induction of chordin.
 ...
PMID:FGF signaling is required for {beta}-catenin-mediated induction of the zebrafish organizer. 1687 84

Using embryos transgenic for the TOP-GFP reporter, we show that the two zebrafish beta-catenins have different roles in the organizer and germ-ring regions of the embryo. beta-Catenin-activated transcription in the prospective organizer region specifically requires beta-catenin-2, whereas the ventrolateral domain of activated transcription is abolished only when both beta-catenins are inhibited. chordin expression during zebrafish gastrulation has been previously shown in both axial and paraxial domains, but is excluded from ventrolateral domains. We show that this gene is expressed in paraxial territories adjacent to the domain of ventrolateral beta-catenin-activated transcription, with only slight overlap, consistent with the now well-known inhibitory effects of Wnt8 on dorsal gene expression. Eliminating both Wnt8/beta-catenin signaling and organizer activity by inhibition of expression of the two beta-catenins results in massive ectopic circumferential expression of chordin and later, by formation of a distinctive embryonic phenotype ('ciuffo') that expresses trunk and anterior neural markers with correct relative anteroposterior patterning. We show that chordin expression is required for this neural gene expression. The Nodal gene squint has been shown to be necessary for optimal expression of chordin and is sufficient in some contexts for its expression. However, chordin is not normally expressed in the ventrolateral germ-ring despite robust expression of squint in this domain. We show the ectopic circumferential expression of chordin and other dorsal genes to be completely dependent on Nodal and FGF signaling, and to be independent of a functional organizer. We propose that whereas the axial domain of chordin expression is formed by cells that are derived from the organizer, the paraxial domain is the result of axial-derived anti-Wnt signals, which relieve the repression that otherwise is set by the Wnt8/beta-catenin/vox,vent pathway on latent germ-ring Nodal/FGF-activated expression.
 ...
PMID:Chordin expression, mediated by Nodal and FGF signaling, is restricted by redundant function of two beta-catenins in the zebrafish embryo. 1768 15

The Frizzled (Fz) receptor is required cell autonomously in Wnt/beta-catenin and planar cell polarity (PCP) signaling. In addition to these requirements, Fz acts nonautonomously during PCP establishment: wild-type cells surrounding fz(-) patches reorient toward the fz(-) cells. The molecular mechanism(s) of nonautonomous Fz signaling are unknown. Our in vivo studies identify the extracellular domain (ECD) of Fz, in particular its CRD (cysteine rich domain), as critical for nonautonomous Fz-PCP activity. Importantly, we demonstrate biochemical and physical interactions between the FzECD and the transmembrane protein Van Gogh/Strabismus (Vang/Stbm). We show that this function precedes cell-autonomous interactions and visible asymmetric PCP factor localization. Our data suggest that Vang/Stbm can act as a FzECD receptor, allowing cells to sense Fz activity/levels of their neighbors. Thus, direct Fz-Vang/Stbm interactions represent an intriguing mechanism that may account for the global orientation of cells within the plane of their epithelial field.
 ...
PMID:The frizzled extracellular domain is a ligand for Van Gogh/Stbm during nonautonomous planar cell polarity signaling. 1880 40

Formation of the organizer is one of the most central patterning events in vertebrate development. Organizer-derived signals are responsible for establishing the CNS and patterning the dorsal ventral axis. The mechanisms promoting organizer formation are known to involve cooperation between Nodal and Wnt signalling. However, the organizer forms in a very restricted region, suggesting the presence of mechanisms that repress its formation. Here, we show in zebrafish that the transcription factor Sox3 represses multiple steps in the signalling events that lead to organizer formation. Although beta-catenin, Bozozok and Squint are known to play major roles in establishing the dorsal organizer in vertebrate embryos, overexpression of any of these is insufficient to induce robust expression of markers of the organizer in ectopic positions in the animal pole, where Sox3 is strongly expressed. We show that a dominant-negative nuclear localisation mutant of Sox3 can cause ectopic expression of organizer genes via a mechanism that activates all of these earlier factors, resulting in later axis duplication including major bifurcations of the CNS. We also find that the related SoxB1 factor, Sox19b, can act redundantly with Sox3 in these effects. It therefore seems that the broad expression of these SoxB1 genes throughout the early epiblast and their subsequent restriction to the ectoderm is a primary regulator of when and where the organizer forms.
 ...
PMID:SoxB1 transcription factors restrict organizer gene expression by repressing multiple events downstream of Wnt signalling. 2061 Apr 82


<< Previous 1 2