The zebrafish bozozok locus encodes Dharma, a homeodomain protein essential for induction of gastrula organizer and dorsoanterior embryonic structures

Development ◽  
1999 ◽  
Vol 126 (7) ◽  
pp. 1427-1438 ◽  
Author(s):  
K. Fekany ◽  
Y. Yamanaka ◽  
T. Leung ◽  
H.I. Sirotkin ◽  
J. Topczewski ◽  
...  
Keyword(s):  
Normal Development ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Beta Catenin ◽  
Dorsal Midline ◽  
Vertebrate Embryo ◽  
Parallel Pathway ◽  
Embryonic Shield ◽  
Essential Function ◽  
Anterior Patterning

The dorsal gastrula organizer plays a fundamental role in establishment of the vertebrate axis. We demonstrate that the zebrafish bozozok (boz) locus is required at the blastula stages for formation of the embryonic shield, the equivalent of the gastrula organizer and expression of multiple organizer-specific genes. Furthermore, boz is essential for specification of dorsoanterior embryonic structures, including notochord, prechordal mesendoderm, floor plate and forebrain. We report that boz mutations disrupt the homeobox gene dharma. Overexpression of boz in the extraembryonic yolk syncytial layer of boz mutant embryos is sufficient for normal development of the overlying blastoderm, revealing an involvement of extraembryonic structures in anterior patterning in fish similarly to murine embryos. Epistatic analyses indicate that boz acts downstream of beta-catenin and upstream to TGF-beta signaling or in a parallel pathway. These studies provide genetic evidence for an essential function of a homeodomain protein in beta-catenin-mediated induction of the dorsal gastrula organizer and place boz at the top of a hierarchy of zygotic genes specifying the dorsal midline of a vertebrate embryo.

Coding sequence and expression of the homeobox gene Hox 1.3

Development ◽  
1988 ◽  
Vol 102 (2) ◽  
pp. 349-359 ◽  
Author(s):  
M. Fibi ◽  
B. Zink ◽  
M. Kessel ◽  
A.M. Colberg-Poley ◽  
S. Labeit ◽  
...  
Keyword(s):  
Homeobox Gene ◽  
Cell System ◽  
T Antigen ◽  
Open Reading Frame ◽  
Homeodomain Protein ◽  
Chromosome 11 ◽  
3T3 Cells ◽  
Exon 2 ◽  
Reading Frame ◽  
3T3 Fibroblasts

We have characterized Hox 1.3 (previously described as m2), a murine homeobox-containing gene, which is a member of the Hox 1 cluster located on chromosome 6. A cloned cDNA was isolated from an Okayama-Berg library generated from the chemically transformed cell line MB66 MCA ACL6. The protein sequence of 270 amino acids was deduced from the nucleotide sequence of an open reading frame containing the homeobox. The open reading frame is interrupted at the genomic level by a 960 bp intron and is organized in two exons. The Hox 1.3 protein was found to contain extensive sequence homology with the murine homeodomain protein Hox 2.1, which is encoded on chromosome 11. There are two homology with the regions in the first exon, i.e. a hexapeptide conserved in many homeobox-containing genes and the N-terminal domain, which was found to be homologous only to Hox 2.1. Furthermore, in exon 2 the homologies of the homeodomain regions are extended up to the carboxy terminus of Hox 1.3 and Hox 2.1. During prenatal murine development, maximal expression of Hox 1.3 is observed in 12-day embryonic tissue. The two transcripts carrying the Hox 1.3 homeobox are 1.9 kb and about 4 kb in length. An abundant Hox 1.3-specific 1.9 kb RNA is also found in F9 cells which were induced for parietal endoderm differentiation, whereas F9 teratocarcinoma stem cells do not stably express this specific RNA. Induction of the transcript occurs immediately after retinoic acid/cAMP treatment and the RNA level remains high for 5 days. Thus, the kinetics are different from the previously described homeobox transcripts Hox 1.1 and Hox 3.1. Interestingly, by analogy to the F9 cell system a negative correlation between transformation and Hox 1.3 expression is observed in 3T3 fibroblasts also. Untransformed 3T3 cells carry abundant 1.9 kb Hox 1.3 RNA, whereas the methylcholanthrene-transformed MB66 and LTK- cells or 3T3 cells transformed by the oncogenes src, fos or SV40 T antigen express only low levels.

bozozok and squint act in parallel to specify dorsal mesoderm and anterior neuroectoderm in zebrafish

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2583-2592 ◽  
Author(s):  
H.I. Sirotkin ◽  
S.T. Dougan ◽  
A.F. Schier ◽  
W.S. Talbot
Keyword(s):  
Neural Development ◽  
Mutational Analysis ◽  
Homeobox Gene ◽  
Beta Catenin ◽  
Neural Patterning ◽  
Blastula Stage ◽  
Mesoderm Development ◽  
Dorsal Mesoderm ◽  
Family Gene ◽  
Bmp Antagonists

In vertebrate embryos, maternal (beta)-catenin protein activates the expression of zygotic genes that establish the dorsal axial structures. Among the zygotically acting genes with key roles in the specification of dorsal axial structures are the homeobox gene bozozok (boz) and the nodal-related (TGF-(beta) family) gene squint (sqt). Both genes are expressed in the dorsal yolk syncytial layer, a source of dorsal mesoderm inducing signals, and mutational analysis has indicated that boz and sqt are required for dorsal mesoderm development. Here we examine the regulatory interactions among boz, sqt and a second nodal-related gene, cyclops (cyc). Three lines of evidence indicate that boz and sqt act in parallel to specify dorsal mesoderm and anterior neuroectoderm. First, boz requires sqt function to induce high levels of ectopic dorsal mesoderm, consistent with sqt acting either downstream or in parallel to boz. Second, sqt mRNA is expressed in blastula stage boz mutants, indicating that boz is not essential for activation of sqt transcription, and conversely, boz mRNA is expressed in blastula stage sqt mutants. Third, boz;sqt double mutants have a much more severe phenotype than boz and sqt single mutants. Double mutants consistently lack the anterior neural tube and axial mesoderm, and ventral fates are markedly expanded. Expression of chordin and noggin1 is greatly reduced in boz;sqt mutants, indicating that the boz and sqt pathways have overlapping roles in activating secreted BMP antagonists. In striking contrast to boz;sqt double mutants, anterior neural fates are specified in boz;sqt;cyc triple mutants. This indicates that cyc represses anterior neural development, and that boz and sqt counteract this repressive function. Our results support a model in which boz and sqt act in parallel to induce dorsalizing BMP-antagonists and to counteract the repressive function of cyc in neural patterning.

Requirements of Lim1, a Drosophila LIM-homeobox gene, for normal leg and antennal development

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4315-4323 ◽  
Author(s):  
T. Tsuji ◽  
A. Sato ◽  
I. Hiratani ◽  
M. Taira ◽  
K. Saigo ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Border Cells ◽  
Null Mutant ◽  
Tarsal Segment ◽  
Segment Boundary ◽  
Leg Development ◽  
Antagonistic Interactions

During Drosophila leg development, the distal-most compartment (pretarsus) and its immediate neighbour (tarsal segment 5) are specified by a pretarsus-specific homeobox gene, aristaless, and tarsal-segment-specific Bar homeobox genes, respectively; the pretarsus/tarsal-segment boundary is formed by antagonistic interactions between Bar and pretarsus-specific genes that include aristaless (Kojima, T., Sato, M. and Saigo, K. (2000) Development 127, 769–778). Here, we show that Drosophila Lim1, a homologue of vertebrate Lim1 encoding a LIM-homeodomain protein, is involved in pretarsus specification and boundary formation through its activation of aristaless. Ectopic expression of Lim1 caused aristaless misexpression, while aristaless expression was significantly reduced in Lim1-null mutant clones. Pretarsus Lim1 expression was negatively regulated by Bar and abolished in leg discs lacking aristaless activity, which was associated with strong Bar misexpression in the presumptive pretarsus. No Lim1 misexpression occurred upon aristaless misexpression. The concerted function of Lim1 and aristaless was required to maintain Fasciclin 2 expression in border cells and form a smooth pretarsus/tarsal-segment boundary. Lim1 was also required for femur, coxa and antennal development.

A class act: conservation of homeodomain protein functions

Development ◽  
1994 ◽  
Vol 1994 (Supplement) ◽  
pp. 61-77 ◽  
Author(s):  
J. Robert Manak ◽  
Matthew P. Scott
Keyword(s):  
Gene Function ◽  
Target Genes ◽  
Hox Genes ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Animal Development ◽  
Protein Functions ◽  
Unified View ◽  
Protein Classes ◽  
And Function

Dramatic successes in identifying vertebrate homeobox genes closely related to their insect relatives have led to the recognition of classes within the homeodomain superfamily. To what extent are the homeodomain protein classes dedicated to specific functions during development? Although information on vertebrate gene functions is limited, existing evidence from mice and nematodes clearly supports conservation of function for the Hox genes. Less compelling, but still remarkable, is the conservation of other homeobox gene classes and of regulators of homeotic gene expression and function. It is too soon to say whether the cases of conservation are unique and exceptional, or the beginning of a profoundly unified view of gene regulation in animal development. In any case, new questions are raised by the data: how can the differences between mammals and insects be compatible with conservation of homeobox gene function? Did the evolution of animal form involve a proliferation of new homeodomain proteins, new modes of regulation of existing gene types, or new relationships with target genes, or is evolutionary change largely the province of other classes of genes? In this review, we summarize what is known about conservation of homeobox gene function.

Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function

Development ◽  
1997 ◽  
Vol 124 (15) ◽  
pp. 2923-2934 ◽  
Author(s):  
K.M. Wassarman ◽  
M. Lewandoski ◽  
K. Campbell ◽  
A.L. Joyner ◽  
J.L. Rubenstein ◽  
...  
Keyword(s):  
Normal Development ◽  
Motor Nerve ◽  
Homeobox Gene ◽  
Neural Plate ◽  
Mouse Embryos ◽  
Loss Of Function ◽  
Isthmic Nuclei ◽  
Signaling Center ◽  
Derivatives Of ◽  
Anterior Posterior

Analysis of mouse embryos homozygous for a loss-of-function allele of Gbx2 demonstrates that this homeobox gene is required for normal development of the mid/hindbrain region. Gbx2 function appears to be necessary at the neural plate stage for the correct specification and normal proliferation or survival of anterior hindbrain precursors. It is also required to maintain normal patterns of expression at the mid/hindbrain boundary of Fgf8 and Wnt1, genes that encode signaling molecules thought to be key components of the mid/hindbrain (isthmic) organizer. In the absence of Gbx2 function, isthmic nuclei, the cerebellum, motor nerve V, and other derivatives of rhombomeres 1–3 fail to form. Additionally, the posterior midbrain in the mutant embryos appears to be extended caudally and displays abnormalities in anterior/posterior patterning. The failure of anterior hindbrain development is presumably due to the loss of Gbx2 function in the precursors of the anterior hindbrain. However, since Gbx2 expression is not detected in the midbrain it seems likely that the defects in midbrain anterior/posterior patterning result from an abnormal isthmic signaling center. These data provide genetic evidence for a link between patterning of the anterior hindbrain and the establishment of the mid/hindbrain organizer, and identify Gbx2 as a gene required for these processes to occur normally.

Identifying targets of the rough homeobox gene of Drosophila: evidence that rhomboid functions in eye development

Development ◽  
1992 ◽  
Vol 116 (2) ◽  
pp. 335-346 ◽  
Author(s):  
M. Freeman ◽  
B.E. Kimmel ◽  
G.M. Rubin
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Eye Development ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Dorsoventral Patterning ◽  
Altered Expression ◽  
Enhancer Trap Lines

In order to identify potential target genes of the rough homeodomain protein, which is known to specify some aspects of the R2/R5 photoreceptor subtype in the Drosophila eye, we have carried out a search for enhancer trap lines whose expression is rough-dependent. We crossed 101 enhancer traps that are expressed in the developing eye into a rough mutant background, and have identified seven lines that have altered expression patterns. One of these putative rough target genes is rhomboid, a gene known to be required for dorsoventral patterning and development of some of the nervous system in the embryo. We have examined the role of rhomboid in eye development and find that, while mutant clones have only a subtle phenotype, ectopic expression of the gene causes the non-neuronal mystery cells to be transformed into photoreceptors. We propose that rhomboid is a part of a partially redundant network of genes that specify photoreceptor cell fate.

scholarly journals Six3, a medaka homologue of the Drosophila homeobox gene sine oculis is expressed in the anterior embryonic shield and the developing eye

1998 ◽  
Vol 74 (1-2) ◽  
pp. 159-164 ◽  
Author(s):  
Felix Loosli ◽  
Reinhard W. Köster ◽  
Matthias Carl ◽  
Annette Krone ◽  
Joachim Wittbrodt
Keyword(s):  
Homeobox Gene ◽  
Sine Oculis ◽  
Embryonic Shield

Changing intestinal connective tissue interactions alters homeobox gene expression in epithelial cells

1997 ◽  
Vol 110 (11) ◽  
pp. 1317-1324 ◽  
Author(s):  
I. Duluc ◽  
O. Lorentz ◽  
C. Fritsch ◽  
C. Leberquier ◽  
M. Kedinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Intestine ◽  
Intestinal Epithelium ◽  
Normal Development ◽  
Homeobox Genes ◽  
Xenograft Model ◽  
Homeobox Gene ◽  
Mesenchymal Cell ◽  
Colonic Epithelium ◽  
Small Intestinal

In segmented organs, homeobox genes are involved in axial patterning and cell identity. Much less is known about their role in non-segmented endoderm derivatives such as the digestive epithelium. Using a xenograft model of fetal intestinal anlagen implanted under the skin of nude mice, we have investigated whether the expression of five homeobox genes (HoxA-4, HoxA-9, HoxC-8, Cdx-1 and Cdx-2) is modified when intestinal epithelium undergoes normal development or displays heterodifferentiation in association with heterotopic mesenchyme. In homotypic associations of fetal endoderm and mesenchyme that recapitulate normal development, the overall pattern of homeobox gene expression was maintained: HoxA-9 and HoxC-8 were the highest in the colon and ileum, respectively, and HoxA-4 was expressed all along the intestine; Cdx-1 and Cdx-2 exhibited an increasing gradient of expression from small intestine to colon. Yet, grafting per se caused a faint upregulation of HoxA-9 and HoxC-8 in small intestinal regions in which these genes are not normally expressed, while the endoderm-mesenchyme dissociation-association step provoked a decay of Cdx-1 in the colon. In heterotopic associations of colonic endoderm with small intestinal mesenchyme, the colonic epithelium exhibited heterodifferentiation to a small intestinal-like phenotype. In this case, we observed a decay of HoxA-9 expression and an upregulation of HoxC-8. Additionally, heterodifferentiation of the colonic epithelium was accompanied by a downregulation of Cdx-1 and Cdx-2 to a level similar to that found in the normal small intestine. To demonstrate that mesenchyme-derived cells can influence Cdx-1 and Cdx-2 expression in the bowel epithelium, fetal jejunal endoderm was associated with intestinal fibroblastic cell lines that either support small intestinal-like or colonic-like morphogenesis. A lower expression of both homeobox genes was shown in grafts presenting the small intestinal phenotype than in those showing glandular colonic-like differentiation. Taken together, these results suggest that homeobox genes participate in the control of the positional information and/or cell differentiation in the intestinal epithelium. They also indicate that the level of Cdx-1 and Cdx-2 homeobox gene expression is influenced by epithelial-mesenchymal cell interactions in the intestinal mucosa.

Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1349-1358 ◽  
Author(s):  
A. Pattyn ◽  
M. Hirsch ◽  
C. Goridis ◽  
J.F. Brunet
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Early Stage ◽  
Control Point ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Loss Of Function ◽  
Dorsoventral Patterning ◽  
Cns Neurons ◽  
Mantle Layer

Motor neurons are a widely studied model of vertebrate neurogenesis. They can be subdivided in somatic, branchial and visceral motor neurons. Recent studies on the dorsoventral patterning of the rhombencephalon have implicated the homeobox genes Pax6 and Nkx2.2 in the early divergence of the transcriptional programme of hindbrain somatic and visceral motor neuronal differentiation. We provide genetic evidence that the paired-like homeodomain protein Phox2b is required for the formation of all branchial and visceral, but not somatic, motor neurons in the hindbrain. In mice lacking Phox2b, both the generic and subtype-specific programs of motoneuronal differentiation are disrupted at an early stage. Most motor neuron precursors die inside the neuroepithelium while those that emigrate to the mantle layer fail to switch on early postmitotic markers and to downregulate neuroepithelial markers. Thus, the loss of function of Phox2b in hindbrain motor neurons exemplifies a novel control point in the generation of CNS neurons.

scholarly journals Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cux1

2008 ◽  
Vol 295 (6) ◽  
pp. F1725-F1734 ◽  
Author(s):  
Neal I. Alcalay ◽  
Madhulika Sharma ◽  
Dianne Vassmer ◽  
Brandon Chapman ◽  
Binu Paul ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transgenic Mice ◽  
Kinase Inhibitors ◽  
Kidney Diseases ◽  
Cathepsin L ◽  
Homeobox Gene ◽  
Renal Cysts ◽  
Homeodomain Protein ◽  
Polycystic Kidney ◽  
Cystic Kidneys

Polycystic kidney diseases (PKD) are inherited as autosomal dominant (ADPKD) or autosomal recessive (ARPKD) traits and are characterized by progressive enlargement of renal cysts. Aberrant cell proliferation is a key feature in the progression of PKD. Cux1 is a homeobox gene that is related to Drosophila cut and is the murine homolog of human CDP (CCAAT Displacement Protein). Cux1 represses the cyclin kinase inhibitors p21 and p27, and transgenic mice ectopically expressing Cux1 develop renal hyperplasia. However, Cux1 transgenic mice do not develop PKD. Here, we show that a 246 amino acid deletion in Cux1 accelerates PKD progression in cpk mice. Cystic kidneys isolated from 10-day-old cpk/Cux1 double mutant mice were significantly larger than kidneys from 10-day-old cpk mice. Moreover, renal function was significantly reduced in the Cux1 mutant cpk mice, compared with cpk mice. The mutant Cux1 protein was ectopically expressed in cyst-lining cells, where expression corresponded to increased cell proliferation and apoptosis, and a decrease in expression of the cyclin kinase inhibitors p27 and p21. While the mutant Cux1 protein altered PKD progression, kidneys from mice carrying the mutant Cux1 protein alone were phenotypically normal, suggesting the Cux1 mutation modifies PKD progression in cpk mice. During cell cycle progression, Cux1 is proteolytically processed by a nuclear isoform of the cysteine protease cathepsin-L. Analysis of the deleted sequences reveals that a cathepsin-L processing site in Cux1 is deleted. Moreover, nuclear cathepsin-L is significantly reduced in both human ADPKD cells and in Pkd1 null kidneys, corresponding to increased levels of Cux1 protein in the cystic cells and kidneys. These results suggest a mechanism in which reduced Cux1 processing by cathepsin-L results in the accumulation of Cux1, downregulation of p21/p27, and increased cell proliferation in PKD.

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