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U Rüther

Publications and source records attributed to U Rüther.

At least 19 recordsLinked to original sources
PubMed2001

Bambi is coexpressed with Bmp-4 during mouse embryogenesis.

Signaling of TGF-beta superfamily members is tightly controlled by an elaborate network of regulators (for recent review see Trends Genet. 15 (1999) 3; Genes Dev. 14 (2000) 627). Recently, the transmembrane protein BAMBI (BMP and activin membrane-bound inhibitor) has been shown to interfere with Bmp and activin-like signaling by inhibiting Tgf-beta type I receptor activation (Nature 401 (1999) 480). In striking contrast to other Bmp antagonists like noggin (Cell 86 (1996) 599) or chordin (Cell 86 (1996) 589), BAMBI is strictly coexpressed with Bmp-4 during early Xenopus embryogenesis. The grouping of genes according to their shared complex spatial expression pattern and their involvement in the same biological signaling pathway has been referred to as synexpression group. This concept facilitates prognoses about the roles of a group member with unknown function. Apparently, only a minority of genes is organized in synexpression groups and up to now they have mainly been described in yeast and Xenopus (for review see Nature 402 (1999) 483). In the frog, BAMBI is a member of the Bmp-4 synexpression group (Nature 401 (1999) 480). We identified two murine homologues of BAMBI one of which, named Bambi-psi, is a pseudogene. We show that the spatiotemporal expression pattern of Bambi closely matches that of Bmp-4 during mouse embryonic development. Moreover, we show that Bambi expression is induced in mouse embryonic fibroblasts by Bmp-4. Hence, we provide first evidence for the existence of an evolutionarily conserved Bmp-4 synexpression group in mammals.

Amino Acid Sequence↗
PubMed2001

Expression of Irx6 during mouse morphogenesis.

Iroquois (Irx) proteins comprise a family of homeodomain-containing transcription factors involved in patterning and regionalization of embryonic tissues in both vertebrates and invertebrates. The six murine Irx genes are organized in two clusters, each consisting of three genes. Irx1, Irx2 and Irx4 belong to the IrxA cluster on chromosome 13, whereas Irx3, Irx5 and Irx6, comprising the IrxB cluster, are located on chromosome 8 (Peters et al., Genome Res. 10 (2000) 1453). Developmental expression patterns have so far only been reported for five Irx genes. Here, we investigated the expression pattern of Irx6 during mouse morphogenesis and early organogenesis. The pattern was found to be much more restricted compared to the other five Irx genes, and its level of expression was much lower.

Animals↗
PubMed2001

Gene and cluster-specific expression of the Iroquois family members during mouse development.

Mammalian homologues of the Drosophila Iroquois homeobox gene complex, involved in patterning and regionalization of differentiation, have recently been identified (Mech. Dev., 69 (1997) 169; Dev. Biol., 217 (2000) 266; Dev. Dyn., 218 (2000) 160; Mech. Dev., 91 (2000) 317; Dev. Biol., 224 (2000) 263; Genome Res., 10 (2000) 1453; Mech. Dev., 103 (2001) 193). The six members of the murine family were found to be organized in two cognate clusters of three genes each, Irx1, -2, -4 and Irx3, -5, -6, respectively (Peters et al., 2000). As a basis for further study of their regulation and function we performed a comparative analysis of the genomic organization and of the expression patterns of all six Irx genes. The genes are expressed in highly specific and regionalized patterns of ectoderm, mesoderm and endoderm derived tissues. In most tissues the pattern of expression of the clustered genes, especially of Irx1 and -2 and of Irx3 and -5, respectively, closely resembled each other while those of Irx4 and -6 were very divergent. Interestingly, the expression of cognate genes was found to be mutually exclusive in adjacent and interacting tissues of limb, heart and the laryncho-pharyncheal region. The results indicate that the Irx genes are coordinately regulated at the level of the cluster.

Animals↗
PubMed2001

Herpesvirus saimiri Tip gene causes T-cell lymphomas in transgenic mice.

New World primates develop T-cell lymphomas on infection with Herpesvirus saimiri. To investigate the oncogenic potential of the Tip gene of Herpesvirus saimiri strain C488, we tried to establish transgenic mice that should express Tip under control of a constitutive promoter. Although transgene-positive embryos were found, lines could not be established. However, using a system in which the transgene has to be activated by a Cre recombinase-mediated deletion, we were able to obtain several Tip transgenic lines. At high expression levels, the mice developed T-cell lymphomas. Thus, Tip can induce lymphomas and is therefore very likely responsible for the oncogenicity of Herpesvirus saimiri.

Animals↗
PubMed2001

Serum response factor is required for immediate-early gene activation yet is dispensable for proliferation of embryonic stem cells.

Addition of serum to mitogen-starved cells activates the cellular immediate-early gene (IEG) response. Serum response factor (SRF) contributes to such mitogen-stimulated transcriptional induction of many IEGs during the G0-G1 cell cycle transition. SRF is also believed to be essential for cell cycle progression, as impairment of SRF activity by specific antisera or antisense RNA has previously been shown to block mammalian cell proliferation. In contrast, Srf(-/-) mouse embryos grow and develop up to E6.0. Using the embryonic stem (ES) cell system, we demonstrate here that wild-type ES cells do not undergo complete cell cycle arrest upon serum withdrawal but that they can mount an efficient IEG response. This IEG response, however, is severely impaired in Srf(-/-) ES cells, providing the first genetic proof that IEG activation is dependent upon SRF. Also, Srf(-/-) ES cells display altered cellular morphology, reduced cortical actin expression, and an impaired plating efficiency on gelatin. Yet, despite these defects, the proliferation rates of Srf(-/-) ES cells are not substantially altered, demonstrating that SRF function is not required for ES cell cycle progression.

Animals↗
PubMed2000

Srf(-/-) ES cells display non-cell-autonomous impairment in mesodermal differentiation.

The serum response factor (SRF) transcription factor is essential for murine embryogenesis. SRF+(-/-) embryos stop developing at the onset of gastrulation, lacking detectable mesoderm. This developmental defect may reflect cell-autonomous impairment of SRF(-/-) embryonic cells in mesoderm formation. Alternatively, it may be caused by a non-cell-autonomous defect superimposed upon inappropriate provision of mesoderm-inducing signals to primitive ectodermal cells. We demonstrate that the ability of SRF(-/-) embryonic stem (ES) cells to differentiate in vitro into mesodermal cells is indeed impaired. However, this impairment can be modulated by external, cell-independent factors. Retinoic acid, but not dimethylsulfoxide, permitted activation of the mesodermal marker gene T(Bra), which was also activated when SRF was expressed in SRF(-/-) ES cells. Embryoid bodies from SRF(-/-) ES cell aggregates also activated mesodermal marker genes, but displayed unusual morphologies and impairment in cavitation. Finally, in nude mice, Srf(-/-) ES cells readily differentiated into mesodermal cells of SRF(-/-) genotype, including cartilage, bone or muscle cells. We demonstrate that SRF contributes to mesodermal gene expression of ES cells and that SRF(-/-) ES cells display a non-cell-autonomous defect in differentiation towards mesoderm.

Animals↗
PubMed2000

Fra-1 replaces c-Fos-dependent functions in mice.

Structure-function analysis as well as studies with knock-out and transgenic mice have assigned distinct functions to c-Fos and Fra-1, two components of the transcription factor AP-1 (activator protein-1). To test whether Fra-1 could substitute for c-Fos, we generated knock-in mice that express Fra-1 in place of c-Fos. Fra-1 rescues c-Fos-dependent functions such as bone development and light-induced photoreceptor apoptosis. Importantly, rescue of bone cell differentiation, but not photoreceptor apoptosis, is gene-dosage dependent. Moreover, Fra-1 fails to substitute for c-Fos in inducing expression of target genes in fibroblasts. These results show that c-Fos and Fra-1 have maintained functional equivalence during vertebrate evolution.

Animals↗
PubMed2000

First-line high-dose chemotherapy +/- radiation therapy in patients with metastatic germ-cell cancer and brain metastases.

PURPOSE: To examine the feasibility and efficacy of first-line high-dose chemotherapy (HD-CTX) in patients with advanced metastatic germ-cell tumors (GCT) and brain metastases. PATIENTS AND METHODS: Twenty-two patients with brain metastases at initial diagnosis were identified within a cohort of two hundred thirty-one consecutive patients with advanced metastatic disease, entered on a German multicenter trial between January 1993 and July 1998. All patients received first-line HD-CTX with cisplatin-etoposide-ifosfamide (HD-VIP) followed by autologous stem-cell transplantation. Brain irradiation (BRT) with 30-50 Gy +/- 10 Gy boost was applied in patients with symptomatic CNS disease or as consolidation in case of residual CNS lesions after HD-CTX. RESULTS: A median number of 4 HD-CTX cycles (range 2-5) were applied to the 22 patients. Ten patients received HD-CTX alone and twelve patients were treated with HD-CTX plus BRT. Median duration of WHO grade 4 granulocytopenia and thrombocytopenia was seven and five days after each cycle, respectively. Non-hematologic toxicity consisted mainly of mucositis/enteritis (WHO grade 3-4 32%). Two early deaths occurred in twenty-two patients (one CNS-bleeding/one sepsis). Fourteen of twenty patients achieved a CR/PRm- status. Twenty patients (91%) responded in the brain (55% CR/36% PR). Two-year progression-free and overall survival rates were 72% and 81%, respectively. These survival rates are substantially higher compared to the available data in the literature. CONCLUSIONS: High-dose chemotherapy with autologous stem-cell support +/- BRT appears to be feasible without increased therapy-related mortality in patients with advanced metastatic GCT and brain metastases. The results achieved emphasize the high chemosensitivity of CNS metastases from GCT and suggest a potential role for dose intensification. The dose of BRT in addition to HD-CTX may be tailored to the presence of clinical symptoms and the response of CNS metastases to chemotherapy.

Adult↗
PubMed2000

Organization of mouse Iroquois homeobox genes in two clusters suggests a conserved regulation and function in vertebrate development.

Iroquois proteins comprise a conserved family of homeodomain-containing transcription factors involved in patterning and regionalization of embryonic tissues in both vertebrates and invertebrates. Earlier studies identified four murine Iroquois (Irx) genes. Here we report the isolation of two additional members of the murine gene family, Irx5 and Irx6. Phylogenetic analysis of the Irx gene family revealed distinct clades for fly and vertebrate genes, and vertebrate members themselves were classified into three pairs of cognate genes. Mapping of the murine Irx genes identified two gene clusters located on mouse chromosomes 8 and 13, respectively. Each gene cluster is represented by three Irx genes whose relative positions within both clusters are strictly conserved. Combined results from phylogenetic, linkage, and physical mapping studies provide evidence for the evolution of two Irx gene clusters by duplication of a larger chromosomal region and dispersion to two chromosomal locations. The maintenance of two cognate Irx gene clusters during vertebrate evolution suggests that their genomic organization is important for the regulation, expression, and function of Irx genes during embryonic development.

Amino Acid Sequence↗
PubMed2000

Second malignancies following pure seminoma.

PURPOSE: Second malignancies in patients with pure testicular seminoma were studied in order to look for adverse late effects of treatment and to study the significance of second malignancies during follow-up. PATIENTS, METHODS: In a multicentric investigation, 839 consecutive patients with pure testicular seminoma were observed for a median follow-up of 3.9 years. Thirty-seven patients had been excluded from the study because they already had had either a contralateral testicular germ cell tumor or another malignancy. 758 patients received radiotherapy, 76 underwent chemotherapy, 5 had surveillance only. The expected rate of second cancers was calculated according to the data of the cancer registry of Saarland, Germany. RESULTS: Twenty-two second cancers (13 contralateral testicular tumors, 9 extratesticular malignancies) were recorded. The overall risk of having a second cancer was RR = 4.8 (95% CI 3. 0-7.3). The risk of having a subsequent testicular tumor is RR = 44. 8 (95% Cl 23.9-76.7). 1.1% of the patients developed a nontesticular second tumor. The risk of having a nontesticular second cancer is RR = 2.1 (95% CI 1.0-4.0). A significantly increased risk was observed for renal cell cancer as well (RR = 12.5; 95% Cl: 1.5-45.1). Increased RR without reaching statistical significance were found for rectal cancer (RR = 5.0; 95% Cl: 0.1-27.9) and non-Hodgkin lymphoma (RR = 6.7; 95% CI 0.2-37.1). None of the second cancers were directly located within the radiation field; 5 neoplasms arose at the border of the radiation field. CONCLUSIONS: This study confirmed the increased risk of having a second testicular germ cell cancer. There is also a small but definitely increased overall risk of having a nontesticular second cancer. Treatment-unrelated factors - possibly genetic predisposition - must be considered for a substantial number of these second tumors, since in the present study the follow-up was rather short and most of the second cancers were located outside of the radiation fields. In particular, the association of renal cancer with testicular cancer appears to be a more than chance occurrence. Second cancer is a real hazard following treatment of testicular cancers and should always be considered during follow-up.

Adult↗
PubMed2000

Transcriptional activity of GLI1 is negatively regulated by protein kinase A.

The transcription factor GLI1 is one of three vertebrate members of the GLI family, which is characterized by a highly conserved DNA-binding domain of five zinc fingers. We have analyzed whether human GLI1 is a target of PKA regulation. It was found that PKA inhibits GLI1 transcriptional activity. However, no evidence for proteolytic processing or for alteration in the subcellular distribution of GLI1 was obtained. The responsive PKA site (aa333-336) was localized to the second zinc finger of GLI1. Mutation of Ser336 revealed that PKA could also stimulate GLI1 transcriptional activity. Thus, our data demonstrate both negative and positive regulation of human GLI1 by PKA.

Animals↗
PubMed1999

Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells.

Bone morphogenetic proteins (BMPs) are morphogenetic signaling molecules essential for embryonic patterning. To obtain molecular insight into the influence of BMPs on morphogenesis, we searched for new genes directly activated by BMP signaling. In vitro cultured mouse embryonic stem (ES) cells were used, cultivated in chemically defined growth medium (CDM). CDM-cultured ES cells responded very selectively to stimulation by various mesoderm inducers (BMP2/4, activin A, and basic fibroblast growth factor). BMP2/4 rapidly induced transcript levels of the homeobox genes Msx-1 and Msx-2 and the proto-oncogene JunB, whereas c-jun transcripts displayed delayed albeit prolonged increase. Using differential display cDNA cloning, six direct BMP target genes were identified. These include Id3, which showed strong mRNA induction, and the moderately induced Cyr61, DEK, and eIF4AII genes, as well as a gene encoding a GC-binding protein. Besides Id3, also the Id1 and Id2 genes were activated by BMP4 in both ES cells and a range of different cell lines. Id genes encode negative regulators of basic helix-loop-helix transcription factors. In vivo we observed local ectopic expression of Id3 and Msx-2 mRNAs in Ft/+ embryos at overlapping regions of ectopic Bmp4 misexpression. We therefore propose that the Msx and Id genes are direct target genes of embryonic BMP4 signaling in vivo.

Animals↗
PubMed1999

[The rare differential diagnosis of a mediastinal space-occupying lesion].

HISTORY AND CLINICAL FINDINGS: Two months before admission a 31-year-old man first noted a painless swelling on the right side of his neck without any associated symptoms. Physical examination revealed a painless right cervical node 4 cm in diameter. INVESTIGATIONS: Magnetic resonance imaging demonstrated a large right-sided cervical tumour which extended into a mediastinal mass 11 cm in diameter. The excised cervical node showed a Hodgkin's lymphoma. Further tests to stage the disease revealed a 1.5 cm tumour in the right testis. Removal of the latter showed a mixed testicular tumour. Mediastinoscopic biopsy confirmed Hodgkin's lymphoma of the mediastinal mass. TREATMENT AND COURSE: Standard chemotherapy of the Hodgkin's lymphoma was undertaken, followed by "extended field" radiation which has so far secured a remission of two years. CONCLUSION: Histological diagnosis is always essential in the case of an unusual tumour location so that a synchronous second tumour may be revealed. If there is a second tumour, exact histological classification with definitive staging of the tumours is necessary to ensure adequate treatment.

Adult↗
PubMed1999

Mouse Dac, a novel nuclear factor with homology to Drosophila dachshund shows a dynamic expression in the neural crest, the eye, the neocortex, and the limb bud.

Dac is a novel nuclear factor in mouse and humans that shares homology with Drosophila dachshund (dac). Alignment with available sequences defines a conserved box of 117 amino acids that shares weak homology with the proto-oncogene Ski and Sno. Dac expression is found in various neuroectodermal and mesenchymal tissues. At early developmental stages Dac is expressed in lateral mesoderm and in neural crest cells. In the neural plate/tube Dac expression is initially seen in the prosencephalon and gets gradually restricted to the presumptive neocortex and the distal portion of the outgrowing optic vesicle. Furthermore, Dac transcripts are detected in the mesenchyme underlying the Apical Ectodermal Ridge (AER) of the extending limb bud, the dorsal root ganglia and chain ganglia, and the mesenchyme of the growing genitalia. Dac expression in the Gli 3 mutant extra toes (Xt/Xt) shows little difference compared to the expression in wild-type limb buds. In contrast, a significant expansion of Dac expression are observed in the anterior mesenchyme of the limb buds of hemimelic extra toes (Hx/+) mice. FISH analysis reveals that human DAC maps to chromosome 13q22.3-23 and further fine-mapping defined a position of the DAC gene at 54cM or 13q21.1, a locus that associates with mental retardation and skeletal abnormalities.

Amino Acid Sequence↗
PubMed1999

The mouse mutation Pdn (Polydactyly Nagoya) is caused by the integration of a retrotransposon into the Gli3 gene.

Mutations in the Gli3 gene are associated with a preaxial polydactyly in several mouse mutants such as extra-toes (Xt). The semidominant mouse mutant Pdn (Polydactyly Nagoya) is characterized by a mild polydactyly on the anterior side of the hind limbs. Homozygous Pdn mice show a more severe polydactyly, additional skeletal malformations, and abnormal brain development. Herein, we report the molecular basis of Pdn, being the integration of an Early Transposon (ETn) into the Gli3 gene. As a consequence, several novel Gli3 mRNAs are generated by alternatively spliced transcripts.

Amino Acid Sequence↗
PubMed1999

Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation.

The Fused toes (Ft) mouse mutation was created by insertional mutagenesis, resulting in the deletion of several hundred kb of genomic sequences of mouse Chromosome (Chr) 8. Mice heterozygous for the Ft mutation are characterized by partial syndactyly of forelimbs and massive thymic hyperplasia indicating that programmed cell death is affected. Homozygous Ft/Ft embryos die at midgestation and show severe malformations of craniofacial structures. Furthermore, establishment of left-right asymmetry is random. Here we report on the positional cloning of a novel gene by exon trap analysis of a genomic clone encoding wild-type sequences corresponding to parts of the deletion in Ft mutants. RT-PCR experiments demonstrated that the newly identified gene, Fatso (Fto), is expressed throughout embryonic development. Wide expression was also found in tissues of adult mice. We show that expression of Fto is completely absent in mouse embryonic fibroblasts homozygous for the Ft mutation. In addition, we isolated the full-length cDNA which encodes a putative 58-kDa protein showing no similarities to known proteins or protein motifs. The expression data of Fto define it as a candidate gene involved in processes such as programmed cell death, craniofacial development, and establishment of left-right asymmetry.

Amino Acid Sequence↗
PubMed1999

Gli genes and limb development.

During development of the limb Shh plays a key role as a mediator of zone of polarizing activity (ZPA). However, the molecular mechanisms by which Shh directs anterior/posterior patterning in the limb remain unknown. Members of the Gli gene family encode zinc-finger transcription factors and represent likely candidates for being regulators of Shh target genes. In this review we would like to summarize the current knowledge on expression and function of Gli genes in limb development.

Animals↗