The genetic map around the tail kinks (tk) locus on mouse chromosome 9.

in Mammalian Genome (1993), 4(10), 560-4

Tail kinks (tk) is a classical mouse skeletal mutation, located on Chromosome (Chr) 9. As the first step for the positional cloning of the tk gene, we have established a genetic map of a region ... [more ▼]

Tail kinks (tk) is a classical mouse skeletal mutation, located on Chromosome (Chr) 9. As the first step for the positional cloning of the tk gene, we have established a genetic map of a region surrounding the tk locus by generating a backcross segregating for tk. From this backcross, 1004 progeny were analyzed for the coat-color phenotype of the proximally located dilute (d) gene and for the distally flanking microsatellite marker, D9Mit12. Fifty-six recombinants between d and tk and 75 recombinants between tk and D9Mit12 were identified, completing a panel of 130 recombinants including one double recombinant. This panel allowed us to map five microsatellite loci as well as d and Mod-1 with respect to tk. We show that one of the microsatellite markers mapped, D9Mit9, does not recombine at all with tk in our backcross. This indicates that the D9Mit9 locus will serve as a good starting point for a chromosomal walk to the tk gene. [less ▲]

A new Pax gene, Pax-9, maps to mouse chromosome 12.

in Mammalian Genome (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 ▲]

Pax1, a member of the paired box-containing class of developmental control genes, is mapped to human chromosome 20p11.2 by in situ hybridization (ISH and FISH).

in Genomics (1992), 14(3), 740-4

Pax-1, a member of a murine multigene family, belongs to the paired box-containing class of developmental control genes first identified in Drosophila. The Pax-1 gene encodes a sequence-specific DNA ... [more ▼]

Pax-1, a member of a murine multigene family, belongs to the paired box-containing class of developmental control genes first identified in Drosophila. The Pax-1 gene encodes a sequence-specific DNA-binding protein with transcriptional activating properties and has been found to be mutated in the autosomal recessive mutation undulated (un) on mouse chromosome 2 with vertebral anomalies along the entire rostrocaudal axis. By radioactive in situ hybridization (ISH) using a fragment from the murine Pax-1 paired box that is almost identical to the respective sequences from the cognate human gene HuP48 and fluorescence in situ hybridization (FISH) using a complete mouse Pax-1 cDNA, we have assigned the human homologue of murine Pax-1, the PAX1 locus, to chromosome 20p. The map position of PAX1 after FISH (FL-pter value of 0.34 +/- 0.04) corresponds to band p11.2. These results confirm the exceptional homology between human chromosome 20 and the distal segment of mouse chromosome 2, extending from bands F to G, and add PAX1 to the group of genes on 20p like PTPA, PRNP, SCG1, BMP2A, which are located in proximity on both chromosomes. [less ▲]

Development of the skeletal system.

in Ciba Foundation Symposium (1992), 165

The analysis of the development of the skeletal system has been greatly facilitated by the availability of a large number of mouse mutants with skeletal defects. Whereas for many of these mutants a ... [more ▼]

The analysis of the development of the skeletal system has been greatly facilitated by the availability of a large number of mouse mutants with skeletal defects. Whereas for many of these mutants a description of the main phenotypic abnormalities is known, molecular insight into the ontogeny of the skeletal system is limited. One of the few skeletal mutants for which the molecular basis is known is undulated. These mice have a defect in the differentiation of the sclerotome and Pax-1, a mouse paired-box containing gene, has been identified as a candidate gene for this mutation. A molecular analysis of three independent undulated alleles revealed that in each case the Pax-1 gene is affected. One of the alleles could be classified as a null allele, in which the Pax-1 gene is deleted. A phenotypic analysis shows that Pax-1 is required for proper differentiation of intervertebral discs and vertebral bodies. [less ▲]

Pax: a murine multigene family of paired box-containing genes.

in Genomics (1991), 11(2), 424-34

A murine multigene family has been identified that shares a conserved sequence motif, the paired box, with developmental control and tissue-specific genes of Drosophila. To date five murine paired box ... [more ▼]

A murine multigene family has been identified that shares a conserved sequence motif, the paired box, with developmental control and tissue-specific genes of Drosophila. To date five murine paired box-containing genes (Pax genes) have been described and one, Pax-1, has been associated with the developmental mutant phenotype undulated. Here we describe the paired boxes of three novel Pax genes, Pax-4, Pax-5, and Pax-6. Comparison of the eight murine paired domains of the mouse, the five Drosophila paired domains, and the three human paired domains shows that they fall into six distinct classes: class I comprises Pox meso, Pax-1, and HuP48; class II paired, gooseberry-proximal, gooseberry-distal, Pax-3, Pax-7, HuP1, and HuP2; class III Pax-2, Pax-5, and Pax-8; class IV Pax-4; class V Pox neuro; and class VI Pax-6. Pax-1 and the human gene HuP48 have identical paired domains, as do Pax-3 and HuP2 as well as Pax-7 and HuP1, and are likely to represent homologous genes in mouse and man. Identical intron-exon structure and extensive sequence homology of their paired boxes suggest that several Pax genes represent paralogs. The chromosomal location of all novel Pax genes and of Pax-3 and Pax-7 has been determined and reveals that they are not clustered. [less ▲]

Separate elements cause lineage restriction and specify boundaries of Hox-1.1 expression.

in Development (1991), 112(1), 279-87

The Hox genes are a class of putative developmental control genes that are thought to be involved in the specification of positional identity along the anteroposterior axis of the vertebrate embryo. It is ... [more ▼]

The Hox genes are a class of putative developmental control genes that are thought to be involved in the specification of positional identity along the anteroposterior axis of the vertebrate embryo. It is apparent from their expression pattern that their regulation is dependent upon positional information. In a previous analysis of the Hox-1.1 promoter in transgenic mice, we identified sequences that were sufficient to establish transgene expression in a specific region of the embryo. The construct used, however, did not contain enough regulatory sequences to reproduce all aspects of Hox-1.1 expression. In particular, neither a posterior boundary nor a restriction of expression to prevertebrae was achieved. Here we show correct regulation by Hox-1.1 sequences in transgenic mice and identify the elements responsible for different levels of control. Concomitant with the subdivision of mesodermal cells into different lineages during gastrulation and organogenesis, Hox-1.1 expression is restricted to successively smaller sets of cells. Distinct elements are required at different stages of development to execute this developmental programme. One position-responsive element (130 bp nontranslated leader) was shown to be crucial for the restriction of expression not only along the anteroposterior axis of the embryo, setting the posterior border, but also along the dorsoventral axis of the neural tube and to the lineage giving rise to the prevertebrae. Thus, Hox-1.1 expression is established in a specific region of the embryo and in a specific lineage of the mesoderm by restricting the activity of the promoter by the combined effect of several regulatory elements. [less ▲]

Variations of cervical vertebrae after expression of a Hox-1.1 transgene in mice.

in Cell (1990), 61(2), 301-8

To understand the function of murine homeobox genes, a genetic analysis is mandatory. We generated gain-of-function mutants by introducing genomic sequences of the Hox-1.1 gene under the control of a ... [more ▼]

To understand the function of murine homeobox genes, a genetic analysis is mandatory. We generated gain-of-function mutants by introducing genomic sequences of the Hox-1.1 gene under the control of a chicken beta-actin promoter into mice. Our previous data had shown that these transgenic mice are nonviable after birth and are born with craniofacial abnormalities. In a subsequent detailed analysis of severely affected animals, malformations of the basioccipital bone, the atlas, and the axis were observed. Manifestation of an additional vertebra, a proatlas, occurred at the craniocervical transition. The dominant interference of the Hox-1.1 transgene with developmental programs seems to occur around day 9 of gestation, the time of neural crest migration and somite differentiation. We discuss the resulting phenotype with respect to a developmental control function of Hox-1.1. [less ▲]

Position-specific activity of the Hox1.1 promoter in transgenic mice.

in Development (1990), 108(3), 435-42

During development, positional values have to be assigned to groups of cells. The murine Hox genes are a class of genes that are predicted to be involved at some stage in this process. During ... [more ▼]

During development, positional values have to be assigned to groups of cells. The murine Hox genes are a class of genes that are predicted to be involved at some stage in this process. During embryogenesis they are expressed in distinct overlapping region- and stage-specific patterns and therefore must be regulated in response to positional information. In this study, we have analysed the activity of Hox1.1 promoter sequences in transgenic mice. The use of lacZ as a marker allows a detailed analysis of expression at the single cell level during early embryonic development. We show that 3.6 kbp of promoter and 1.7 kbp of 3' sequences provide sufficient regulatory information to express a transgene in a spatial and temporal manner indistinguishable from the endogenous Hox1.1 gene during the period of development when Hox1.1 expression is established. The activation occurs in a strict order in specific ectodermal and mesodermal domains. Within each of these domains the transgene is activated over a period of four hours apparently randomly in single cells. In a following second period, Hox1.1 and transgene expression patterns diverge. In this period, transgene expression persists in many mesodermally derived cells that do not express Hox1.1 indicating the absence of a negative regulatory element in the transgene. The anterior boundary of transgene expression is identical to that of Hox1.1. However, no posterior boundary of transgene expression is set, suggesting that a separate element absent from the transgene specifies this boundary. [less ▲]

Analysis of the spatial and temporal control of Hox 1.1 in transgenic mice

in Development (1990), (108), 435-442

Tumorigenesis and eye abnormalities in transgenic mice expressing MSV-SV40 large T-antigen.

in Oncogene (1990), 5(2), 225-32

Transgenic mice which expressed SV40 large T-antigen under the control of the MSV enhancer and the SV40 promoter were generated. In animals containing an intact MSV enhancer, total lens cataracts and ... [more ▼]

Transgenic mice which expressed SV40 large T-antigen under the control of the MSV enhancer and the SV40 promoter were generated. In animals containing an intact MSV enhancer, total lens cataracts and neuroectodermal brain tumors, originating in the pineal organ were observed. In contrast, 5' deletion of the MSV enhancer to a residual 53 bp resulted in a different spectrum of pathologies. Whilst lens cataracts still occurred, no brain tumors could be detected. Instead, fibrosarcomas and adenocarcinomas of the kidneys were induced. In addition, tumors of the endocrine pancreas were observed with both transgene constructs. We conclude that the MSV enhancer element is sufficient to direct the expression of the viral reporter gene to the lens and the pineal organ in transgenic mice. Deletion of the MSV enhancer correlates with the loss of DNA elements responsible for the pineal cell specific expression of SV40 large T-antigen. [less ▲]