References of "Koseki, H"
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See detailZic1 regulates the patterning of vertebral arches in cooperation with Gli3.
Aruga, J.; Mizugishi, K.; Koseki, H. et al

in Mechanisms of Development (1999), 89(1-2), 141-50

Skeletal abnormalities are described that appeared in Zic1-deficient mice. These mice show multiple abnormalities in the axial skeleton. The deformities are severe in the dorsal parts of the vertebrae ... [more ▼]

Skeletal abnormalities are described that appeared in Zic1-deficient mice. These mice show multiple abnormalities in the axial skeleton. The deformities are severe in the dorsal parts of the vertebrae, vertebral arches, but less so in the vertebral bodies (spina bifida occulta). The proximal ribs are deformed having ectopic processes. The abnormalities found in the vertebral arches can be traced back to disturbed segmental patterns of dorsal sclerotome. The Zic1/Gli3 double mutants showed severe abnormalities of vertebral arches not found in single mutants. The abnormalities in the vertebral arches were less severe in Zic1/Pax1 mutants than Zic1/Gli3 mutants, but significantly more pronounced than in Zic1 single mutants. The three genes may act synergistically in the development of the vertebral arches. [less ▲]

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See detailNotochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development.
Furumoto, T. A.; Miura, N.; Akasaka, T. et al

in Developmental Biology (1999), 210(1), 15-29

During axial skeleton development, the notochord is essential for the induction of the sclerotome and for the subsequent differentiation of cartilage forming the vertebral bodies and intervertebral discs ... [more ▼]

During axial skeleton development, the notochord is essential for the induction of the sclerotome and for the subsequent differentiation of cartilage forming the vertebral bodies and intervertebral discs. These functions are mainly mediated by the diffusible signaling molecule Sonic hedgehog. The products of the paired-box-containing Pax1 and the mesenchyme forkhead-1 (Mfh1) genes are expressed in the developing sclerotome and are essential for the normal development of the vertebral column. Here, we demonstrate that Mfh1 like Pax1 expression is dependent on Sonic hedgehog signals from the notochord, and Mfh1 and Pax1 act synergistically to generate the vertebral column. In Mfh1/Pax1 double mutants, dorsomedial structures of the vertebrae are missing, resulting in extreme spina bifida accompanied by subcutaneous myelomeningocoele, and the vertebral bodies and intervertebral discs are missing. The morphological defects in Mfh1/Pax1 double mutants strongly correlate with the reduction of the mitotic rate of sclerotome cells. Thus, both the Mfh1 and the Pax1 gene products cooperate to mediate Sonic hedgehog-dependent proliferation of sclerotome cells. [less ▲]

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See detailPax genes and organogenesis.
Dahl, E.; Koseki, H.; Balling, Rudi UL

in BioEssays : news and reviews in molecular, cellular and developmental biology (1997), 19(9), 755-65

Pax genes are a family of developmental control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding ... [more ▼]

Pax genes are a family of developmental control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing genes were detected in Drosophila melanogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out of nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (PAX3), Aniridia (PAX6), Peter's anomaly (PAX6), renal coloboma syndrome (PAX2) or spontaneous mouse mutants (undulated (Pax1), Splotch (Pax3), Small eye (Pax6), Pax2(1)Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax genes are involved in pattern formation during embryogenesis, possibly by determining the time and place of organ initiation or morphogenesis. For most tissues, however, the nature of the primary developmental action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position-specific regulation of cell proliferation. [less ▲]

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See detailA role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton.
Akasaka, T.; Kanno, M.; Balling, Rudi UL et al

in Development (1996), 122(5), 1513-22

Segment identity in both invertebrates and vertebrates is conferred by spatially restricted distribution of homeotic gene products. In Drosophila, the expression of Homeobox genes during embryogenesis is ... [more ▼]

Segment identity in both invertebrates and vertebrates is conferred by spatially restricted distribution of homeotic gene products. In Drosophila, the expression of Homeobox genes during embryogenesis is initially induced by segmentation gene products and then maintained by Polycomb group and Trithorax group gene products. Polycomb group gene homologs are conserved in vertebrates. Murine mel-18 and closely related bmi-1 are homologous to posterior sex combs and suppressor two of zeste. Mel-18 protein mediates a transcriptional repression via direct binding to specific DNA sequences. To gain further insight into the function of Mel-18, we have inactivated the mel-18 locus by homologous recombination. Mice lacking mel-18 survive to birth and die around 4 weeks after birth after exhibiting strong growth retardation. Similar to the Drosophila posterior sex combs mutant, posterior transformations of the axial skeleton were reproducibly observed in mel-18 mutants. The homeotic transformations were correlated with ectopic expression of Homeobox cluster genes along the anteroposterior axis in the developing paraxial mesoderm. Surprisingly, mel-18-deficient phenotypes are reminiscent of bmi-1 mutants. These results indicate that the vertebrate Polycomb group genes mel-18 and bmi-1, like Drosophila Polycomb group gene products, might play a crucial role in maintaining the silent state of Homeobox gene expression during paraxial mesoderm development. [less ▲]

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See detailPax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation.
Wallin, J.; Eibel, H.; Neubuser, A. et al

in Development (1996), 122(1), 23-30

Pax1 is a transcriptional regulatory protein expressed during mouse embryogenesis and has been shown to have an important function in vertebral column development. Expression of Pax1 mRNA in the embryonic ... [more ▼]

Pax1 is a transcriptional regulatory protein expressed during mouse embryogenesis and has been shown to have an important function in vertebral column development. Expression of Pax1 mRNA in the embryonic thymus has been reported previously. Here we show that Pax1 protein expression in thymic epithelial cells can be detected throughout thymic development and in the adult. Expression starts in the early endodermal epithelium lining the foregut region and includes the epithelium of the third pharyngeal pouch, a structure giving rise to part of the thymus epithelium. In early stages of thymus development a large proportion of thymus cells expresses Pax1. With increasing age, the proportion of Pax1-expressing cells is reduced and in the adult mouse only a small fraction of cortical thymic stromal cells retains strong Pax1 expression. Expression of Pax1 in thymus epithelium is necessary for establishing the thymus microenvironment required for normal T cell maturation. Mutations in the Pax-1 gene in undulated mice affect not only the total size of the thymus but also the maturation of thymocytes. The number of thymocytes is reduced about 2- to 5-fold, affecting mainly the CD4+8+ immature and CD4+ mature thymocyte subsets. The expression levels of major thymocyte surface markers remains unchanged with the exception of Thy-1 which was found to be expressed at 3- to 4-fold higher levels. [less ▲]

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See detailDevelopment of the vertebral column: Morphogenesis and genes
Wilting, J; Müller, T S; Ebensperger, C et al

in Vorgel, R; Fanghaenel, J; Giebel, J (Eds.) Aspects of Teratologie (1996)

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See detailExpression of avian Pax1 and Pax9 is intrinsically regulated in the pharyngeal endoderm, but depends on environmental influences in the paraxial mesoderm.
Muller, Tim UL; Ebensperger, C.; Neubuser, A. et al

in Developmental Biology (1996), 178(2), 403-17

Pax1 and Pax9 represent a subfamily of paired-box-containing genes. In vertebrates, Pax1 and Pax9 transcripts have been found specifically in mesodermal tissues and the pharyngeal endoderm. Pax1 ... [more ▼]

Pax1 and Pax9 represent a subfamily of paired-box-containing genes. In vertebrates, Pax1 and Pax9 transcripts have been found specifically in mesodermal tissues and the pharyngeal endoderm. Pax1 expression in the sclerotomes has been shown to be indispensable for proper formation of the axial skeleton, but expression of Pax1 in the endoderm has not been studied in detail. We have cloned the chick homologue of the murine Pax9 gene. Our results show that transcripts of Pax1 and Pax9 are first detectable in the prospective foregut endoderm of headfold-stage avian embryos. Endodermal expression correlates with the highly proliferative zones of the folding foregut and evaginating pharyngeal pouches. In later stages, Pax1 and Pax9 are expressed in overlapping but distinct patterns within the developing sclerotomes and limb buds. From grafting experiments we conclude that activation of pharyngeal Pax1 and Pax9 expression is an intrinsic property of the endoderm, not requiring midline structures or head mesoderm. In contrast, notochord is required to induce Pax1 in competent sclerotomes. Here we show that in vitro there is a cranio-caudal gradient of inductive capacity in the notochord. This coincides with the graded expression of Pax1 and Pax9 along the cranio-caudal axis in 2- to 3-day-old embryos. Furthermore, paraxial head mesoderm shows no competence to express Pax1. Finally, in vitro we find counteracting influences on notochord signaling by lateral tissues (lateral plate, intermediate mesoderm), leading to an inhibition of Sonic hedgehog (Shh) expression in notochord and floor plate, as well as Pax1 and Pax9 expression in sclerotomes. Taken together, our results demonstrate that different mechanisms regulate expression of Pax1 and Pax9 in foregut and sclerotome, but suggest a common function for both genes in the two tissues that is promoting proliferation and preventing fusion of neighboring blastemas. [less ▲]

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See detailCharacterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1.
Neubuser, A.; Koseki, H.; Balling, Rudi UL

in Developmental Biology (1995), 170(2), 701-16

Pax9, a recently identified mouse paired-box-containing gene, is highly homologous to Pax1 and belongs to the same subfamily as Pax1, Hup48, PAX9, and pox meso. Two overlapping cDNA clones spanning the ... [more ▼]

Pax9, a recently identified mouse paired-box-containing gene, is highly homologous to Pax1 and belongs to the same subfamily as Pax1, Hup48, PAX9, and pox meso. Two overlapping cDNA clones spanning the entire coding region of Pax9 were isolated and sequenced. A comparison of the Pax1 and -9 protein sequences reveals a high degree of similarity even outside the paired box, while the carboxy-terminus of the two proteins diverges completely. We demonstrate that Pax9 can bind to the e5 sequence from the Drosophila even skipped promoter, which is also recognized by Pax1. We analyzed the expression of Pax9 during embryogenesis of wildtype, Undulated short-tail (Uns), and Danforth's short tail (Sd) mice. In wildtype embryos Pax9 is expressed in the pharyngeal pouches and their derivatives, the developing vertebral column, the tail, the head, and the limbs. Expression of Pax9 is unaffected in Uns embryos, in which the Pax1 gene is deleted, arguing that expression of Pax9 is not dependent on Pax1. The expression of Pax9 is lost in the caudal part of Sd homozygous embryos, suggesting that expression of Pax9 in the vertebral column is dependent on the notochord. These results indicate that both Pax9 and -1 may act in parallel during morphogenesis of the vertebral column. [less ▲]

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See detailPax-1, a regulator of sclerotome development is induced by notochord and floor plate signals in avian embryos.
Ebensperger, C.; Wilting, J.; Brand-Saberi, B. et al

in Anatomy & Embryology (1995), 191(4), 297-310

Pax-1 encodes for a DNA-binding transcriptional activator that was originally discovered in murine embryos using a probe from the Drosophila paired-box-containing gene, gooseberry-distal. We have cloned ... [more ▼]

Pax-1 encodes for a DNA-binding transcriptional activator that was originally discovered in murine embryos using a probe from the Drosophila paired-box-containing gene, gooseberry-distal. We have cloned the avian Pax-1 gene as a basis for experimental studies of the induction of Pax-1 in the paraxial mesoderm. The amino acid sequence of the paired-domain is exactly the same in the quail and mouse, whereas outside the paired-domain there is 61% homology. Starting at about the eight-somite stage, quail Pax-1 is expressed in the paraxial mesoderm in a craniocaudal sequence. The unsegmented paraxial mesoderm and the two most recently formed somites do not express Pax-1. In the epithelial somite, the somitocoele cells and the cells of the ventral two-thirds of the epithelial wall are positive. As soon as the sclerotome is formed, only a subset of sclerotome cells expresses Pax-1. These are the cells that migrate towards the notochord to form the perinotochordal tube. Expression then becomes restricted to the intervertebral discs, the perichondrium of the vertebral bodies and the connective tissue surrounding the spinal ganglia. Additional expression domains are found in the scapula and the pelvic region, distinct areas of the head, and the epithelium of the second to the fourth visceral pouch. In later stages the thymus is positive. In vitro and in vivo experiments show that the notochord induces Pax-1 in the paraxial mesoderm, but limb bud mesoderm is not competent to respond to notochordal signals. Floor plate is also capable of inducing Pax-1 expression in sclerotome cells. Our studies show that in competent cells of the paraxial mesoderm, Pax-1 is a mediator of signals emanating from the notochord and the floor plate. [less ▲]

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See detailThe role of Pax-1 in axial skeleton development.
Wallin, J.; Wilting, J.; Koseki, H. et al

in Development (1994), 120(5), 1109-21

Previous studies have identified a single amino-acid substitution in the transcriptional regulator Pax-1 as the cause of the mouse skeletal mutant undulated (un). To evaluate the role of Pax-1 in the ... [more ▼]

Previous studies have identified a single amino-acid substitution in the transcriptional regulator Pax-1 as the cause of the mouse skeletal mutant undulated (un). To evaluate the role of Pax-1 in the formation of the axial skeleton we have studied Pax-1 protein expression in early sclerotome cells and during subsequent embryonic development, and we have characterized the phenotype of three different Pax-1 mouse mutants, un, undulated-extensive (unex) and Undulated short-tail (Uns). In the Uns mutation the whole Pax-1 locus is deleted, resulting in the complete absence of Pax-1 protein in these mice. The other two genotypes are interpreted as hypomorphs. We conclude that Pax-1 is necessary for normal vertebral column formation along the entire axis, although the severity of the phenotype is strongest in the lumbar region and the tail. Pax-1-deficient mice lack vertebral bodies and intervertebral discs. The proximal part of the ribs and the rib homologues are also missing or severely malformed, whereas neural arches are nearly normal. Pax-1 is thus required for the development of the ventral parts of vertebrae. Embryonic analyses reveal that although sclerotomes are formed in mutant embryos, abnormalities can be detected from day 10.5 p.c. onwards. The phenotypic analyses also suggest that the notochord still influences vertebral body formation some days after the sclerotomes are formed. Furthermore, the notochord diameter is larger in mutant embryos from day 12 p.c., due to increased cell proliferation. In the strongly affected genotypes the notochord persists as a rod-like structure and the nucleus pulposus is never properly formed. Since the notochord is Pax-1-negative these findings suggest a bidirectional interaction between notochord and paraxial mesoderm. The availability of these Pax-1 mutant alleles permitted us to define an early role for Pax-1 in sclerotome patterning as well as a late role in intervertebral disc development. Our observations suggest that Pax-1 function is required for essential steps in ventral sclerotome differentiation, i.e. for the transition from the mesenchymal stage to the onset of chondrogenesis. [less ▲]

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See detailMouse genetics and the development of vertebral column development
Balling, Rudi UL; Koseki, H; Wallin, J et al

in Proceedings Greenwood Genetics Center (1994), (13), 58-60

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See detailA new Pax gene, Pax-9, maps to mouse chromosome 12.
Wallin, J.; Mizutani, Y.; Imai, K. et al

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (1993), 4(7), 354-8

Members of the Pax gene family have recently been shown to play important roles in mouse embryogenesis. Of eight so far characterized Pax genes, three have been associated with mouse developmental mutants ... [more ▼]

Members of the Pax gene family have recently been shown to play important roles in mouse embryogenesis. Of eight so far characterized Pax genes, three have been associated with mouse developmental mutants. Here we report the cloning of a new Pax gene, Pax-9. Most of the DNA sequence encoding the highly conserved paired domain has been determined and compared with previously known paired domains. This comparison classifies Pax-9 as a member of the same subgroup as Pax-1/undulated. By analysis of the segregation of a Pax-9 restriction fragment length polymorphism and a large number of simple sequence length polymorphisms in an interspecific C57BL/6 x Mus musculus mollosinus backcross, Pax-9 was mapped close to the D12Nds1 locus on the proximal part of Chromosome (Chr) 12. [less ▲]

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See detailFine genetic mapping of the proximal part of mouse chromosome 2 excludes Pax-8 as a candidate gene for Danforth's short tail (Sd).
Koseki, H.; Zachgo, J.; Mizutani, Y. et al

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (1993), 4(6), 324-7

Danforth's short tail (Sd) is a semidominant mutation of the mouse with effects on the skeleton and the urogenital system. In view of its phenotype and its position in the proximal part of Chromosome (Chr ... [more ▼]

Danforth's short tail (Sd) is a semidominant mutation of the mouse with effects on the skeleton and the urogenital system. In view of its phenotype and its position in the proximal part of Chromosome (Chr) 2, three genes qualified as possible candidates: Pax-8, a paired box-containing gene; Midkine (Mdk), a retinoic acid-responsive gene; and a new locus (Etl-4) identified by enhancer trapping with a lacZ reporter gene which showed expression in the notochord, the mesonephric mesenchyme, and the apical ectodermal ridge. Three different backcrosses involving all three genes in different combinations were set up and analyzed. From our results we conclude that Sd, Etl-4, Pax-8, and Mdk are independent loci, with Etl-4 being the closest genetic marker (1.1 +/- 1.4 cM) to the Danforth's short tail (Sd) gene. [less ▲]

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See detailThe genetics of skeletal development.
Balling, Rudi UL; Ebensperger, C.; Hoffmann, I. et al

in Annales de Génétique (1993), 36(1), 56-62

A genetic analysis of biologic processes has provided substantial advances in developmental biology. Whereas the genetic analysis of Drosophila is a potent system, recently developed tools have enabled a ... [more ▼]

A genetic analysis of biologic processes has provided substantial advances in developmental biology. Whereas the genetic analysis of Drosophila is a potent system, recently developed tools have enabled a genetic analysis of the development of vertebrates. For these studies, numerous mouse mutants are available and many more will be introduced in the near future. Mutations involving the skeleton are easy to detect. This article reports the phenotype and molecular analysis of two mutant mouse strains with skeletal abnormalities, undulated (un) and Danforth's short tail (Sd). The role of the corresponding genes in skeletal development of these two mutants and the basis for their genetic interaction are discussed. [less ▲]

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See detailA role for Pax-1 as a mediator of notochordal signals during the dorsoventral specification of vertebrae.
Koseki, H.; Wallin, J.; Wilting, J. et al

in Development (1993), 119(3), 649-60

The notochord plays an important role in the differentiation of the paraxial mesoderm and the neural tube. We have analyzed the role of the notochord in somite differentiation and subsequent formation of ... [more ▼]

The notochord plays an important role in the differentiation of the paraxial mesoderm and the neural tube. We have analyzed the role of the notochord in somite differentiation and subsequent formation of the vertebral column using a mouse mutant, Danforth's short-tail (Sd). In this mutant, the skeletal phenotype is most probably a result of degeneration and subsequent loss of the notochord. The Sd gene is known to interact with undulated (un), a sclerotome mutant. Double mutants between Sd and un alleles show an increase in the severity of the defects, mainly in the ventral parts of the vertebrae. We also show that part of the Sd phenotype is strikingly similar to that of the un alleles. As un is known to be caused by a mutation in the Pax-1 gene, we analyzed Pax-1 expression in Sd embryos. In Sd embryos, Pax-1 expression is reduced, providing a potential molecular basis for the genetic interaction observed. A complete loss of Pax-1 expression in morphologically intact mesenchyme was found in the lower thoracic-lumbar region, which is phenotypically very similar to the corresponding region in a Pax-1 null mutant, Undulated short-tail. The sclerotome developmental abnormalities in Sd coincide closely, both in time and space, with notochordal changes, as determined by whole-mount T antibody staining. These findings indicate that an intact notochord is necessary for normal Pax-1 expression in sclerotome cells, which is in turn required for the formation of the ventral parts of the vertebrae. The observed correlation among structural changes of the notochord, Pax-1 expression levels and skeletal phenotypes, suggests that Pax-1 might be an intrinsic mediator of notochordal signals during the dorsoventral specification of vertebrae. [less ▲]

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