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Query: UMLS:C0038379 (strabismus)
 9,317 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vertebrates, specification of the dorso-ventral axis requires Wnt signaling, which leads to formation of the Nieuwkoop center and the Spemann organizer (dorsal organizer), through the nuclear accumulation of beta-catenin. Zebrafish bozozok/dharma (boz) and squint (sqt), which encode a homeodomain protein and a Nodal-related protein, respectively, are required for the formation of the dorsal organizer. The zygotic expression of boz and sqt in the dorsal blastoderm and dorsal yolk syncytial layer (YSL) was dependent on the maternally derived Wnt signal, and their expression at the late blastula and early gastrula stages was dependent on the zygotic expression of their own genes. The dorsal organizer genes, goosecoid (gsc) and chordin (din), were ectopically expressed in wild-type embryos injected with boz or sqt RNA. The expression of gsc strictly depended on both boz and sqt while the expression of din strongly depended on boz but only partially depended on sqt and cyclops (cyc, another nodal-related gene). Overexpression of boz in embryos defective in Nodal signaling elicited the ectopic expression of din but not gsc and resulted in dorsalization, implying that boz could induce part of the organizer, independent of the Nodal proteins. Furthermore, boz; sqt and boz;cyc double mutants displayed a severely ventralized phenotype with anterior truncation, compared with the single mutants, and boz;sqt;cyc triple mutant embryos exhibited an even more severe phenotype, lacking the anterior neuroectoderm and notochord, suggesting that Boz/Dharma and the Nodal-related proteins cooperatively regulate the formation of the dorsal organizer.
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PMID:Cooperative roles of Bozozok/Dharma and Nodal-related proteins in the formation of the dorsal organizer in zebrafish. 1070 53

Vertebrate endoderm development has recently become the focus of intense investigation. In this report, we first show that the zebrafish bonnie and clyde (bon) gene plays a critical early role in endoderm formation. bon mutants exhibit a profound reduction in the number of sox17-expressing endodermal precursors formed during gastrulation, and, consequently, a profound reduction in gut tissue at later stages. The endodermal precursors that do form in bon mutants, however, appear to differentiate normally indicating that bon is not required at later steps of endoderm development. We further demonstrate that bon encodes a paired-class homeodomain protein of the Mix family that is expressed transiently before and during early gastrulation in both mesodermal and endodermal progenitors. Overexpression of bon can rescue endodermal gene expression and the formation of a gut tube in bon mutants. Analysis of a newly identified mutant allele reveals that a single amino acid substitution in the DNA recognition helix of the homeodomain creates a dominant interfering form of Bon when overexpressed. We also show through loss- and gain-of-function analyses that Bon functions exclusively downstream of cyclops and squint signaling. Together, our data demonstrate that Bon is a critical transcriptional regulator of early endoderm formation.
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PMID:The zebrafish bonnie and clyde gene encodes a Mix family homeodomain protein that regulates the generation of endodermal precursors. 1081 62

Holoprosencephaly (HPE) is the most common structural defect of the developing forebrain in humans (1 in 250 conceptuses, 1 in 16,000 live-born infants). HPE is aetiologically heterogeneous, with both environmental and genetic causes. So far, three human HPE genes are known: SHH at chromosome region 7q36 (ref. 6); ZIC2 at 13q32 (ref. 7); and SIX3 at 2p21 (ref. 8). In animal models, genes in the Nodal signalling pathway, such as those mutated in the zebrafish mutants cyclops (refs 9,10), squint (ref. 11) and one-eyed pinhead (oep; ref. 12), cause HPE. Mice heterozygous for null alleles of both Nodal and Smad2 have cyclopia. Here we describe the involvement of the TG-interacting factor (TGIF), a homeodomain protein, in human HPE. We mapped TGIF to the HPE minimal critical region in 18p11.3. Heterozygous mutations in individuals with HPE affect the transcriptional repression domain of TGIF, the DNA-binding domain or the domain that interacts with SMAD2. (The latter is an effector in the signalling pathway of the neural axis developmental factor NODAL, a member of the transforming growth factor-beta (TGF-beta) family.) Several of these mutations cause a loss of TGIF function. Thus, TGIF links the NODAL signalling pathway to the bifurcation of the human forebrain and the establishment of ventral midline structures.
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PMID:Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. 1083 38

Formation of the three germ layers requires a series of inductive events during early embryogenesis. Studies in zebrafish indicate that the source of these inductive signals may be the extra-embryonic yolk syncytial layer (YSL). The characterization of genes encoding the nodal-related factor, Squint, and homeodomain protein, Bozozok, both of which are expressed in the YSL, suggested that the YSL has a role in mesendoderm induction. However, these genes, and a second nodal-related factor, cyclops, are also expressed in the overlying marginal blastomeres, raising the possibility that the marginal blastomeres can induce mesendodermal genes independently of the YSL. We have developed a novel technique to study signaling from the YSL in which we specifically eliminate RNAs in the YSL, thus addressing the in vivo requirement of RNA-derived signals from this region in mesendoderm induction. We show that injection of RNase into the yolk cell after the 1K cell stage (3 hours) effectively eliminates YSL transcripts without affecting ubiquitously expressed genes in the blastoderm. We also present data that indicate the stability of existing proteins in the YSL is unaffected by RNase injection. Using this technique, we show that RNA in the YSL is required for the formation of ventrolateral mesendoderm and induction of the nodal-related genes in the ventrolateral marginal blastomeres, revealing the presence of an unidentified inducing signal released from the YSL. We also demonstrate that the dorsal mesoderm can be induced independently of signals from the YSL and present evidence that this is due to the stabilization of (&bgr;)-catenin in the dorsal marginal blastomeres. Our results demonstrate that germ layer formation and patterning in zebrafish uses a combination of YSL-dependent and -independent inductive events.
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PMID:The role of the yolk syncytial layer in germ layer patterning in zebrafish. 1102 70

The zebrafish bozozok (boz) gene encoding a homeodomain protein (also named Dharma/Nieuwkoid) is required during blastula stages for the formation of a complete Spemann-Mangold gastrula organizer and subsequent development of axial mesoderm and anterior neural structures. Expression of bozin the dorsal yolk syncytial layer (YSL) and overlying marginal blastomeres is activated by beta-catenin. Bozozok itself acts as a transcriptional repressor, and promotes organizer formation by directly inhibiting expression of the bmp2b (swirl) gene and by negatively regulating Wnt signaling by an unknown mechanism. boz cooperates with the Nodal-related secreted factors, Cyclops and Squint, in organizer formation. The incomplete organizer in boz mutants is deficient in expression of a number of factors such as Chordin that antagonize Bone morphogenetic proteins (Bmps), and Dickkopf 1, a Wnt antagonist. Conversely, the dorsal blastoderm of boz mutants exhibits ectopic expression of genes normally excluded from the dorsal midline such as wnt8 or tbx6. boz specifies the formation of anterior neuroectoderm by regulating Bmp and Wnt pathways in a fashion consistent with Nieuwkoop's two-step neural patterning model. boz promotes neural induction by limiting the anti-neuralizing activity of Bmp morphogens. In addition, by negative regulation of Wnt signaling, boz limits posteriorization of neuroectoderm. bozozok chordino double mutants exhibit a synergistic loss of head and trunk. This synthetic phenotype is due to dramatically increased Bmp signaling and consequent massive accumulation of cells in the tailbud at the expense of dorso-anterior structures. Therefore, boz and din act in overlapping pathways that provide the main mechanism to limit Bmp signaling in the zebrafish gastrula and allow for head and trunk development. Notably, Bozozok appears to function by repressing transcription of target genes such as swr (bmp2b) gene, and as such is the earliest acting repressor that the nascent dorsal axis is using to antagonize ventral influences.
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PMID:The role of the homeodomain protein Bozozok in zebrafish axis formation. 1129 60