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1.
Dev Biol ; 229(1): 128-40, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11133159

ABSTRACT

The Pax family of transcription factors plays important roles in vertebrate organogenesis. Pax-2 is a critical factor in the development of the mammalian urogenital system. Pax-2 is expressed in the epithelia of the ureter, the Müllerian duct, and the Wolffian duct and in the nephrogenic mesenchyme. Gene targeting in the mouse as well as natural mutations in mouse and man have demonstrated the requirement of Pax-2 in the development of these structures. Little is known about the molecular mechanisms regulating Pax-2 expression in the developing urogenital system. As a first step to reveal these mechanisms and to search for the elements and factors controlling Pax-2 expression we have characterized regulatory sequences of the Pax-2 gene in an in vivo reporter assay in the mouse. An 8.5-kb genomic region upstream of the Pax-2 transcription start site directed reporter gene activity in the epithelium of the pronephric duct at 8.25 days postcoitum (dpc) and in the Wolffian duct starting from 9.0 dpc. Expression in the Wolffian duct and its derivatives, the ureter, the collecting duct system, the seminal vesicles, the vas deferens, and the epididymis, was maintained at least until 18.5 dpc. Hence, an element(s) in the 8.5-kb upstream region is sufficient to initiate and maintain Pax-2 expression in the Wolffian duct and its derivatives. In order to more precisely map the Wolffian duct regulatory sequences, a deletion analysis of the 8.5-kb upstream region was performed in a transient in vivo reporter assay. A 0.4-kb subfragment was required for marker gene expression in the Wolffian duct. Misexpression of fgf8 under the control of the 8.5-kb upstream region resulted in polycystic kidneys, demonstrating the general usefulness of Pax-2 regulatory sequences in misexpression of foreign genes in the ureter and collecting duct system of the kidney in transgenic approaches in mice.


Subject(s)
DNA-Binding Proteins/genetics , Regulatory Sequences, Nucleic Acid , Transcription Factors/genetics , Urogenital System/embryology , Wolffian Ducts/embryology , Animals , Base Sequence , Epithelium/embryology , Gene Expression Regulation, Developmental , Genes, Reporter , Genotype , In Situ Hybridization , Mice , Mice, Mutant Strains , Molecular Sequence Data , PAX2 Transcription Factor , Transgenes , Ureter/embryology
2.
Mech Dev ; 100(1): 83-6, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11118889

ABSTRACT

T-box genes encode transcription factors that regulate a variety of developmental processes. In this report, we describe the cloning and expression analysis of the novel mouse T-box gene Tbx18. During development expression is most prominent in the proepicardial organ and in the epicardium of the heart. Other sites of expression include the cranial paraxial mesoderm, the presomitic mesoderm, the anterior somite half, the genital ridge, and the developing limb buds.


Subject(s)
Cloning, Molecular , Embryo, Mammalian/metabolism , Transcription Factors/biosynthesis , Transcription Factors/genetics , Amino Acid Sequence , Animals , Base Sequence , DNA, Complementary/metabolism , Extremities/embryology , In Situ Hybridization , Mesoderm/metabolism , Mice , Molecular Sequence Data , Pericardium/embryology , Phylogeny , Reverse Transcriptase Polymerase Chain Reaction , T-Box Domain Proteins , Time Factors
3.
Mech Dev ; 100(1): 87-91, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11118890

ABSTRACT

T-box genes constitute a conserved multi-gene family with important roles in many developmental processes. In this report, we describe the cloning and expression analysis of a novel mouse T-box gene, Tbx20. Expression is prominent in the extraembryonic mesoderm, in the developing heart, the eye anlage and motor neurons of hindbrain and spinal cord.


Subject(s)
Cloning, Molecular , Embryo, Mammalian/metabolism , T-Box Domain Proteins , Transcription Factors/biosynthesis , Transcription Factors/genetics , Alternative Splicing , Amino Acid Sequence , Animals , Base Sequence , Chick Embryo , DNA, Complementary/metabolism , Eye/embryology , Gene Library , Heart/embryology , In Situ Hybridization , Mesoderm/metabolism , Mice , Molecular Sequence Data , Motor Neurons/metabolism , Rhombencephalon/embryology , Sequence Homology, Amino Acid , Spinal Cord/embryology , Time Factors
4.
Development ; 127(11): 2259-67, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10804169

ABSTRACT

The axial skeleton develops from the sclerotome, a mesenchymal cell mass derived from the ventral halves of the somites, segmentally repeated units located on either side of the neural tube. Cells from the medial part of the sclerotome form the axial perichondral tube, which gives rise to vertebral bodies and intervertebral discs; the lateral regions of the sclerotome will form the vertebral arches and ribs. Mesenchymal sclerotome cells condense and differentiate into chondrocytes to form a cartilaginous pre-skeleton that is later replaced by bone tissue. Uncx4.1 is a paired type homeodomain transcription factor expressed in a dynamic pattern in the somite and sclerotome. Here we show that mice homozygous for a targeted mutation of the Uncx4.1 gene die perinatally and exhibit severe malformations of the axial skeleton. Pedicles, transverse processes and proximal ribs, elements derived from the lateral sclerotome, are lacking along the entire length of the vertebral column. The mesenchymal anlagen for these elements are formed initially, but condensation and chondrogenesis do not occur. Hence, Uncx4.1 is required for the maintenance and differentiation of particular elements of the axial skeleton.


Subject(s)
Axis, Cervical Vertebra/embryology , Homeodomain Proteins/physiology , Ribs/embryology , Animals , Body Patterning , Bone and Bones/abnormalities , Bone and Bones/embryology , Cell Differentiation , Cell Line , Gene Targeting/methods , Homeodomain Proteins/genetics , Mesoderm , Mice , Mice, Knockout , Somites
5.
Dev Dyn ; 213(4): 440-51, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9853965

ABSTRACT

Members of the Wnt family of secreted glycoproteins act as short-range signaling molecules in vertebrate embryogenesis. Previous work has shown that Wnt-4 is required for kidney development. Mice lacking functional Wnt-4 fail to form pretubular cell aggregates. Wnt-4 acts as an autoinducer of the mesenchymal to epithelial transition underlying nephron development. We have identified a member of the gene family encoding secreted frizzled related proteins (sFRP), putative Wnt antagonists, that shows overlapping expression with Wnt-4 in aggregating mesenchyme and simple epithelial bodies during metanephric development. sFRP-2 expression is absent in metanephric mesenchyme of kidneys mutant for Wnt-4 and is coinduced with Wnt-4 in isolated metanephric mesenchyme by cells expressing Wnt-4. The cysteine-rich domain of sFRP-2 binds to Wnt-4 as shown by coimmunoprecipitation experiments. Hence, sFRP-2 is a target of the Wnt-4 signaling pathway in the metanephric kidney and may modulate Wnt-4 signaling. sFRP-2 expression is highly dynamic and specific during other aspects of embryogenesis. sFRP-2 is expressed in subpopulations of ependymal cells in spinal cord and brain, in the developing eye, in limb bud mesenchyme, in the heart, and strongly in skeletogenic condensations of facial bones, suggesting widespread interaction with other members of the Wnt gene family during embryogenesis.


Subject(s)
Kidney/embryology , Proto-Oncogene Proteins/metabolism , Receptors, Neurotransmitter/metabolism , Signal Transduction , Animals , Cell Line, Transformed , Frizzled Receptors , Gene Expression , Humans , In Situ Hybridization , Mice , Receptors, G-Protein-Coupled , Receptors, Neurotransmitter/genetics , Wnt Proteins , Wnt4 Protein
6.
Mol Cell Biol ; 17(11): 6609-17, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9343424

ABSTRACT

Transcriptional coactivators such as p300 and CREB-binding protein (CBP) function as important elements in the transcription factor network, linking individual transactivators via protein-protein interactions to the basal transcriptional machinery. We have investigated whether p300 plays a role in transactivation mediated by C/EBPbeta, a conserved member of the C/EBP family. We show that C/EBPbeta-dependent transactivation is strongly inhibited by adenovirus E1A but not by E1A mutants defective in p300 binding. Ectopic expression of p300 reverses the E1A-dependent inhibition and increases the transactivation potential of C/EBPbeta. Furthermore, we show that C/EBPbeta and p300 interact with each other and demonstrate that the sequences responsible for interaction map to the E1A binding region of p300 and the amino terminus of C/EBPbeta. Finally, we show that the minimal C/EBPbeta binding site of p300 acts as a dominant-negative inhibitor of C/EBPbeta. These observations identify p300 as a bona fide coactivator for C/EBPbeta. C/EBPbeta is highly expressed in the myelomonocytic lineage of the hematopoietic system and cooperates with Myb to activate mim-1, a gene specifically expressed during myelomonocytic differentiation. Recent evidence has shown that Myb recruits CBP (and presumably p300) as a coactivator and, in contrast to C/EBPbeta, interacts with the CREB binding site of p300-CBP. We show that p300 not only stimulates the activity of Myb and C/EBPbeta individually but also increases the synergy between them. Thus, our results reveal a novel function of p300: in addition to linking specific transcription factors to the basal transcriptional machinery, p300 also mediates the cooperation between transactivators interacting with different domains of p300.


Subject(s)
Acetyltransferases , DNA-Binding Proteins/metabolism , Nuclear Proteins/metabolism , Trans-Activators , Transcription Factors/metabolism , Transcriptional Activation , Adenovirus E1A Proteins , Binding Sites , CCAAT-Enhancer-Binding Proteins , DNA-Binding Proteins/antagonists & inhibitors , Genes, Reporter , Models, Genetic , Nuclear Proteins/antagonists & inhibitors , Oncogene Proteins v-myb , Precipitin Tests , Protein Binding , Proteins/metabolism , Repressor Proteins , Retroviridae Proteins, Oncogenic/metabolism , Transcription, Genetic
7.
EMBO J ; 16(6): 1371-80, 1997 Mar 17.
Article in English | MEDLINE | ID: mdl-9135152

ABSTRACT

The retroviral oncogene v-myb is a mutated and truncated version of the c-myb proto-oncogene and encodes a transcription factor (v-Myb) that specifically transforms myelomonocytic cells. Two different variants of v-myb, transduced independently by the oncogenic chicken retroviruses AMV and E26, have been characterized. It is believed that both variants of v-Myb transform myelomonocytic cells by affecting the expression of specific genes; however, no target genes common to both oncogenic viruses have been identified. Here, we describe the identification of a novel v-Myb target gene, designated as tom-1 (target of myb 1). The tom-1 gene has two promoters, one of which is Myb-inducible. tom-1 is expressed at elevated levels in AMV-transformed as well as in E26-transformed myeloid cells. We show that tom-1 activation by v-Myb does not require de novo protein synthesis and that the Myb-inducible tom-1 promoter contains a functional Myb binding site. Thus, tom-1 is the first example of a direct target gene for both oncogenic forms of the v-myb gene. Further analysis of the Myb-inducible tom-1 promoter shows that a C/EBP binding site is juxtaposed to the Myb binding site and that C/EBP is required for the Myb-dependent activation of the promoter. Together with previous work our results suggest that C/EBP may be a general cooperation partner for v-Myb in myelomonocytic cells.


Subject(s)
Avian Leukosis Virus/genetics , Avian Myeloblastosis Virus/genetics , Oncogenes , Amino Acid Sequence , Animals , Base Sequence , CCAAT-Enhancer-Binding Proteins , Cell Transformation, Neoplastic , Cell Transformation, Viral , Chickens , Cloning, Molecular , DNA, Viral/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Viral , Genes, Viral , Molecular Sequence Data , Nuclear Proteins/metabolism , Oncogene Proteins v-myb , Promoter Regions, Genetic , Retroviridae Proteins, Oncogenic/genetics
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