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U Hochgeschwender

Publications and source records attributed to U Hochgeschwender.

At least 19 recordsLinked to original sources
PubMed2006

Proopiomelanocortin heterozygous and homozygous null mutant mice develop pituitary adenomas.

Mice lacking all pro-opiomelanocortin (POMC)-derived peptides have been created by gene targeting of the POMC locus in embryonic stem cells. Phenotypes of the POMC null homozygous mutants include obesity, pigmentation defects, and adrenal insufficiency. Here, we report that both POMC null homozygous and heterozygous mutants also develop pituitary gland tumors, which result in their premature death. The tumors occur with 100% penetrance in both POMC heterozygous and homozygous genotypes. Histological examinations reveal that tumors start from hyperplastic focal points of melanotrophic cells within the intermediate lobe. Based on the morphological and immunohistological features, we have classified the tumors as non-invasive, non-secreting, intermediate lobe adenomas. These findings uncover potential novel roles of melanocortins in the regulation of cell proliferation.

Adenoma↗
PubMed2003

Adrenocorticotropic hormone directly stimulates testosterone production by the fetal and neonatal mouse testis.

Adult Leydig cell steroidogenesis is dependent on LH but fetal Leydig cells can function independently of gonadotropin stimulation. To identify factors that may be involved in regulation of fetal Leydig cells expressed sequence tag libraries from fetal and adult testes were compared, and fetal-specific genes identified. The ACTH receptor [melanocortin type 2 receptor (Mc2r)] was identified within this fetal-specific group. Subsequent real-time PCR studies confirmed that Mc2r was expressed in the fetal testis at 100-fold higher levels than in the adult testis. Incubation of fetal or neonatal testes with ACTH in vitro stimulated testosterone production more than 10-fold, although ACTH had no effect on testes from animals aged 20 d or older. The steroidogenic response of fetal and neonatal testes to a maximally stimulating dose of human chorionic gonadotropin was similar to the response shown to ACTH. The ED(50) for ACTH, measured in isolated fetal and neonatal testicular cells, was 5 x 10(-10) M and the lowest dose of ACTH eliciting a response was 2 x 10(-11) M. Circulating ACTH levels in fetal mice were around 8 x 10(-11) M. Neither alpha-MSH nor gamma-MSH had any effect on androgen production in vitro at any age. Fetal testosterone levels were normal in mice that lack circulating ACTH (proopiomelanocortin-null) indicating that ACTH is not essential for fetal Leydig cell function. Results show that both LH and ACTH can regulate testicular steroidogenesis during fetal development in the mouse and suggest that fetal Leydig cells, but not adult Leydig cells, are sensitive to ACTH stimulation.

Adrenocorticotropic Hormone↗
PubMed2001

Impairment in motor learning of somatostatin null mutant mice.

Somatostatin was first identified as a hypothalamic factor which inhibits the release of growth hormone from the anterior pituitary (somatotropin release inhibitory factor, SRIF). Both SRIF and its receptors were subsequently found widely distributed within and outside the nervous system, in the adult as well as in the developing organism. Reflecting this wide distribution, somatostatin has been implicated regulating a diverse array of biological processes. These include body growth, homeostasis, sensory perception, autonomous functions, rate of intestinal absorption, behavior, including cognition and memory, and developmental processes. We produced null mutant mice lacking somatostatin through targeted mutagenesis. The mutant mice are healthy, fertile, and superficially indistinguishable from their heterozygous and wildtype littermates. A 'first round' phenotype screen revealed that mice lacking somatostatin have elevated plasma growth hormone levels, despite normal body size, and have elevated basal plasma corticosterone levels. In order to uncover subtle and unexpected differences, we carried out a systematic behavioral phenotype screen which identified a significant impairment in motor learning revealed when increased demands were made on motor coordination. Motor coordination and motor learning require an intact cerebellum. While somatostatin is virtually absent from the adult cerebellum, the ligand and its receptor(s) are transiently expressed at high levels in the developing cerebellum. This result suggests the functional significance of transient expression of SRIF and its receptors in the development of the cerebellum.

Animals↗
PubMed2001

Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway.

Leptin deficiency results in a complex obesity phenotype comprising both hyperphagia and lowered metabolism. The hyperphagia results, at least in part, from the absence of induction by leptin of melanocyte stimulating hormone (MSH) secretion in the hypothalamus; the MSH normally then binds to melanocortin-4 receptor expressing neurons and inhibits food intake. The basis for the reduced metabolic rate has been unknown. Here we show that leptin administered to leptin-deficient (ob/ob) mice results in a large increase in peripheral MSH levels; further, peripheral administration of an MSH analogue results in a reversal of their abnormally low metabolic rate, in an acceleration of weight loss during a fast, in partial restoration of thermoregulation in a cold challenge, and in inducing serum free fatty acid levels. These results support an important peripheral role for MSH in the integration of metabolism with appetite in response to perceived fat stores indicated by leptin levels.

Animals↗
PubMed2001

Pronociceptive actions of dynorphin maintain chronic neuropathic pain.

Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli, indicating that dynorphin is not required for initiation of neuropathic pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intrathecal dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain.

Animals↗
PubMed2001

Generation of dynorphin knockout mice.

The opioid system has important roles in controlling pain, reward and addiction, and is implicated in numerous other processes within and outside the nervous system, such as mood states, immune responses, and prenatal developmental processes. The effects of the opioid system are mediated by at least three ligands, enkephalin, endorphin, and dynorphin, which act through the opioid receptors mu, delta, and kappa. In order to dissect the roles of individual components of the opioid system, mutant mice lacking single ligands or receptors are instrumental. We report here on the generation and initial characterization of a mutant mouse strain lacking pre-prodynorphin. Dynorphin 'knockout' mice are viable, healthy, and fertile and show no overt behavioral differences to wildtype littermates. Dynorphin knockout mice constitute a valuable tool for many research areas, among them research into pain, substance abuse, and epilepsy.

Animals↗
PubMed1999

The impact of genomics on mammalian neurobiology.

The benefit of genomics lies in the speeding up of research efforts in other fields of biology, including neurobiology. Through accelerated progress in positional cloning and genetic mapping, genomics has forced us to confront at a much faster pace the difficult problem of defining gene function. Elucidation of the function of identified disease genes and other genes expressed in the Central nervous system has to await conceptual developments in other fields.

Alcoholism↗
PubMed1999

Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.

Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.

Adrenal Glands↗
PubMed1999

Isolation and characterization of the mouse homolog of the preprodynorphin (Pdyn) gene.

We have isolated and sequenced the mouse preprodynorphin gene (Pdyn). The Pdyn gene can encode for six biologically active dynorphin peptides. The predicted mouse preprodynorphin has 90%, 67%, and 66% identity with the predicted rat, porcine, and human preprodynorphins, respectively. Using an RT-PCR technique, we show that the Pdyn gene starts being expressed at embryonic day 12.5, with a steep increase of expression by embryonic day 14.5; in the adult mouse it is expressed in the brain, but not in liver, heart, spleen, or kidney.

Age Factors↗
PubMed1997

Isolation and characterization of the gene encoding the type 5 mouse (Mus musculus) somatostatin receptor (msst5).

We have isolated and determined the nucleotide sequence of the gene for the fifth mouse somatostatin receptor (msst5). The gene can encode a protein of 363 amino acid residues (aa). The deduced aa sequence of msst5 has 97 and 81% identity to the rat and human sst5 respectively, while it has lower identities with the four other mouse sst(n)s (msst1 -- 48%, msst2 -- 55%, msst3 -- 56%, and msst4 -- 52%). We show that msst5 is expressed in brain but not in liver, heart, spleen, or kidney of the adult mouse.

Amino Acid Sequence↗
PubMed1996

Isolation and characterization of the mouse (Mus musculus) somatostatin receptor type-4-encoding gene (mSSTR4).

We have isolated and sequenced the mouse somatostatin receptor subtype-4-encoding gene (mSSTR4). The mSSTR4 gene encodes 384 amino acids (aa). The deduced mouse SSTR4 has 95 and 89% aa identity with the deduced rat and human SSTR4, respectively, while it has lower aa identity with the other mouse subtypes (mSSTR1, 60%; mSSTR2, 47%; mSSTR3, 42%). Using an RT-PCR technique, we show that the mSSTR4 gene is expressed in brain, but not in liver, heart, spleen or kidney of the adult mouse.

Amino Acid Sequence↗
PubMed1994

Redundant genes?

Explore the source record for details and available documents.

Alleles↗
PubMed1994

Rapid identification of gene sequences for transcriptional map assembly by direct cDNA screening of genomic reference libraries.

We have used the direct cDNA screening protocol to identify sequences transcribed in cerebral cortex from a reference library of human Xq28. To derive coding sequences from these genomic clones, we first identified fragments containing transcribed sequences and subjected these to exon trapping or to partial sequencing and analysis by Grail. In a preliminary analysis of three clones, coding sequences from two novel genes expressed in brain were identified. This method allows the rapid identification of coding sequences of genes expressed in specific tissues without recourse to cDNA libraries. The approach is amenable to large scale applications and should be useful for isolating candidate disease genes and in particular for assembling integrated transcriptional maps from large genomic regions.

Amino Acid Sequence↗
PubMed1989

Construction and screening of a genomic library specific for mouse chromosome 16.

We have established a protocol for producing libraries of specific mouse chromosomes. The mouse DNA-containing clones from a genomic library of a hamster-mouse somatic cell hybrid containing only one mouse chromosome are identified by screening with radiolabeled mouse repetitive sequences after specifically blocking hamster repetitive sequences; 95% of the mouse DNA-containing clones are identified. We have applied this protocol in producing a library of mouse chromosome 16, consisting of 14,200 clones or two "chromosome equivalents." Each clone occupies an individual well in a microtiter tray, allowing the entire library to be repeatedly and reproducibly plated and analyzed by hybridization. Further, we have established a protocol for making cDNA probes specifically depleted of highly repetitive sequences for probing libraries of genomic clones. By screening the chromosome 16 library with cDNA probes from mouse liver and brain, we demonstrate the feasibility of identifying expressed sequences and characterizing their patterns of expression. Such chromosome-specific libraries can facilitate the isolation of defined genetic loci as well as form the basis for the production of integrated transcriptional, genetic, and physical maps of entire chromosomes.

Animals↗