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Biomedical subjects

J Götz

Publications and source records attributed to J Götz.

At least 37 records · Page 2Linked to original sources
PubMed1999

The role of protein phosphatase 2A catalytic subunit Calpha in embryogenesis: evidence from sequence analysis and localization studies.

Protein phosphatase 2A (PP2A) constitutes one of the major families of protein serine/threonine phosphatases found in all eukaryotic cells. PP2A holoenzymes are composed of a catalytic subunit complexed with a structural regulatory subunit of 65 kDa. These core subunits associate with regulatory subunits of various sizes to form different heterotrimers which have been purified and evaluated with regard to substrate specificity. In fully differentiated tissues PP2A expression levels are highest in the brain, however, relatively little is known about expression in the developing embryo. In order to determine the composition of PP2A catalytic subunits in the mouse, cDNAs were cloned and the genomic organization of PP2A Calpha was determined. By a gene targeting approach in the mouse, we have previously shown that the absence of the major catalytic subunit of PP2A, Calpha, resulted in embryonic lethality around embryonic day E6.5. No mesoderm was formed which implied that PP2A plays a crucial role in gastrulation. Here, we extended our studies and analyzed wildtype embryos for Calpha expression at subsequent stages of development. After gastrulation is completed, we find high expression of Calpha restricted to the neural folds, which suggests that PP2A plays an additional pivotal role in neurulation.

Amino Acid Sequence↗
PubMed1998

Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Calpha.

Protein phosphatase 2A (PP2A) is a multimeric enzyme, containing a catalytic subunit complexed with two regulatory subunits. The catalytic subunit PP2A C is encoded by two distinct and unlinked genes, termed Calpha and Cbeta. The specific function of these two catalytic subunits is unknown. To address the possible redundancy between PP2A and related phosphatases as well as between Calpha and Cbeta, the Calpha subunit gene was deleted by homologous recombination. Homozygous null mutant mice are embryonically lethal, demonstrating that the Calpha subunit gene is an essential gene. As PP2A exerts a range of cellular functions including cell cycle regulation and cell fate determination, we were surprised to find that these embryos develop normally until postimplantation, around embryonic day 5.5/6.0. While no Calpha protein is expressed, we find comparable expression levels of PP2A C at a time when the embryo is degenerating. Despite a 97% amino acid identity, Cbeta cannot completely compensate for the absence of Calpha. Degenerated embryos can be recovered even at embryonic day 13.5, indicating that although embryonic tissue is still capable of proliferating, normal differentiation is significantly impaired. While the primary germ layers ectoderm and endoderm are formed, mesoderm is not formed in degenerating embryos.

Animals↗
PubMed1998

Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions.

The physiological role of prion protein (PrP) remains unknown. Mice devoid of PrP develop normally but are resistant to scrapie; introduction of a PrP transgene restores susceptibility to the disease. To identify the regions of PrP necessary for this activity, we prepared PrP knockout mice expressing PrPs with amino-proximal deletions. Surprisingly, PrP lacking residues 32-121 or 32-134, but not with shorter deletions, caused severe ataxia and neuronal death limited to the granular layer of the cerebellum as early as 1-3 months after birth. The defect was completely abolished by introducing one copy of a wild-type PrP gene. We speculate that these truncated PrPs may be nonfunctional and compete with some other molecule with a PrP-like function for a common ligand.

Alleles↗
PubMed1996

Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre recombinase-mediated site-specific recombination in embryonic stem cells.

Gene disruptions and deletions of up to 20kb have been generated by homologous recombination with appropriate targeting vectors in murine embryonic stem (ES) cells. Because we could not obtain a deletion of about 200 kb in the mouse amyloid precursor protein gene by the classical technique, we employed strategies involving the insertion of loxP sites upstream and downstream of the region to be deleted by homologous recombination and elicited excision of the loxP-flanked region by introduction of a Cre expression vector into the ES cells. In the first approach, the loxP sequences were inserted in two successive steps and after each step, ES cell clones were isolated and characterized. Deletion of the loxP-flanked sequence was accomplished by introducing the cre gene in a third step. In the second approach, ES cells containing the upstream loxP cassette were electroporated simultaneously with the downstream loxP targeting vector and the Cre expression plasmid. ES cells were obtained that gave rise to chimeric mice capable of germ-line transmission of the deleted amyloid precursor protein allele.

Amino Acid Sequence↗
PubMed1995

Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform.

Microtubule-associated protein tau is the major constituent of the paired helical filament, the main fibrous component of the neurofibrillary lesions of Alzheimer's disease. Tau is an axonal phosphoprotein in normal adult brain. In Alzheimer's disease brain tau is hyperphosphorylated and is found not only in axons, but also in cell bodies and dendrites of affected nerve cells. We report the production and analysis of transgenic mice that express the longest human brain tau isoform under the control of the human Thy-1 promoter. As in Alzheimer's disease, transgenic human tau protein was present in nerve cell bodies, axons and dendrites; moreover, it was phosphorylated at sites that are hyperphosphorylated in paired helical filaments. We conclude that transgenic human tau protein showed pre-tangle changes similar to those that precede the full neurofibrillary pathology in Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations.

Fibroblast growth factor 5 (FGF5) is a secreted signaling protein. Mice homozygous for a predicted null allele of the Fgf5 gene, fgf5neo, produced by gene targeting in embryonic stem cells, have abnormally long hair. This phenotype appears identical to that of mice homozygous for the spontaneous mutation angora (go). The fgf5neo and go mutations fail to complement one another, and exon 1 of Fgf5 is deleted in DNA from go homozygotes, demonstrating that go is a mutant allele of Fgf5. Expression of Fgf5 is detected in hair follicles from wild-type mice and is localized to the outer root sheath during the anagen VI phase of the hair growth cycle. These findings provide evidence that FGF5 functions as an inhibitor of hair elongation, thus identifying a molecule whose normal function is apparently to regulate one step in the progression of the follicle through the hair growth cycle.

Alleles↗
PubMed1994

Steady-state pharmacokinetics of a once-daily theophylline formulation (Euphylong) when given twice daily.

In a multiple-dose crossover study in 18 healthy male volunteers the steady-state pharmacokinetics of Euphylong, which has been designed for once-daily evening administration, was investigated after conventional twice-daily administration. Under both modes of administration 2 plasma level profiles over 24-hours each were taken during steady-state (day 5/6 and day 8/9, respectively), in order to assess the reproducibility from day to day. The extent of absorption (AUC) was equivalent for both dosing schemes. The intentional differences in pharmacokinetic profiles between the once-daily and twice-daily administration were reflected in the maximum concentrations (15.0 vs 12.1 mg/l), the plateau time T75% Cmax (11.5 vs 17.1 hours), the percent peak-trough fluctuation (94 vs 47%) and the nocturnal excess (37 vs 4%). Results are given for day 8/9, but were practically identical on day 5/6. Thus, the twice-daily administration provides very smooth plasma levels over 24 hours, however, at the expense of the loss of the nocturnal excess which is of clinical relevance in the treatment of nocturnal asthma.

Absorption↗
PubMed1991

A somatic cell hybrid panel and DNA probes for physical mapping of human chromosome 7p.

To identify by reverse genetics genes on the short arm of human chromosome 7 expected to be involved in the regulation of human craniofacial and limb development, we have set up a human mouse somatic cell hybrid panel that divides 7p into 9 fragments. The breakpoints are defined by deletions or translocations involving one chromosome 7 in the cells of the human cell fusion partners. Particularly densely covered with these cytogenetic anchor points is the proximal area of 7p within and around 7p13. The number of cytogenetic mapping points within proximal 7p could be increased by four, using two diploid human cell lines with small interstitial deletions in this region for dosage studies. We used Southern blots of this panel to assign to 7q or subregions of 7p more than 300 arbitrary DNA probes or genes that provide reference points for physical mapping of 7p. Three reciprocal translocations with one of the breakpoints in 7p13 mark the location of a gene involved in Greig cephalopolysyndactyly syndrome. To define an area in which we could identify candidates for this developmental gene, we established a macrorestriction map using probes flanking the putative gene region. The Greig translocations were found to be located within a 630-kb NotI restriction fragment.

Animals↗
PubMed1990

Non-tolerance and differential susceptibility to diabetes in transgenic mice expressing major histocompatibility class II genes on pancreatic beta cells.

In insulin-dependent diabetes mellitus aberrant expression of major histocompatibility complex (MHC) class II antigens might induce autoimmune destruction of insulin-producing pancreatic beta cells. Here we demonstrate that already the expression of single MHC class II chains (E alpha k and E beta b) is sufficient to cause diabetes without affecting beta cell morphology and cell numbers. Our transgenes interfere at least in two points of insulin production leading to a severely diabetic phenotype. In one case E beta b expression led to a 10-30-fold decrease of mouse insulin mRNA. In another case E alpha k expression reduced insulin secretion to background levels. In addition, we also found a patchy distribution of both insulin and E alpha k expression, indicating heterogeneity of the beta cell population, without the concomitant development of diabetes. Although the transgenic E alpha k E beta b MHC class II molecules were expressed on the surface of pancreatic beta cells, the transgenic mice did not prove to be tolerant for I-E antigen. Autoimmune reactions remained absent showing that aberrant MHC class II expression on pancreatic beta cells alone is not sufficient for the development of autoimmune diabetes in mice.

Animals↗
PubMed1989

[Cytogenetic detection of Prader-Willi syndrome in infancy].

In the case of characteristic chromosomal deletion of chromosome 15(q11----q13) the diagnosis of the Prader-Willi syndrome can be already confirmed in early infancy as shown in our case report. In this connection cytogenetic high-resolution techniques are indispensable. Cytogenetic and clinical problems are discussed.

Chromosome Banding↗
PubMed1988

Increased methotrexate-induced chromosome breakage in patients with free trisomy 21 and their parents.

Increased susceptibility of chromosomes from peripheral blood lymphocytes to the antimetabolite methotrexate (2 X 10(-6) M) has been found in patients with free trisomy 21 and their parents (N = 14). The level of induced chromatid and chromosome breaks is lowest in normal controls intermediate in patients' mothers and fathers, and highest in trisomy 21 patients. The findings are viewed as a special type of cytogenetic polymorphism or as a defective chromosomal infrastructure, also in the parents of trisomic children.

Adult↗
PubMed1987

Isochromosome (18q) in siblings.

A report is presented on a familial occurrence of isochromosome (18q) in a newborn infant and in a fetus in the 24th week of gestation after amniocentesis.

Abnormalities, Multiple↗
PubMed1984

[Cooperative study on the recurrence of lung tuberculosis in East Germany].

144 patients with bacteriologically positive results were analysed out of 258 relapses of pulmonary tuberculosis within one year (1979/80) to find the causes which are favouring relapses. It has been found that in 28% an inadequate chemotherapy, in 16% uncontrolled use of drugs, and in 13% of cases uncooperative attitude of patients were supposed causes of relapse. Causes of relapse could not be established in 23% of patients. Silicosis and chronic alcoholism were observed in 22% of patients with relapse.

Adolescent↗