A5034724305- Receptor Mechanisms and Signaling
- Genetic and Kidney Cyst Diseases
- Congenital heart defects research
- Epigenetics and DNA Methylation
- Hedgehog Signaling Pathway Studies
- Renal and related cancers
- DNA Repair Mechanisms
- Neuropeptides and Animal Physiology
- Microtubule and mitosis dynamics
- Developmental Biology and Gene Regulation
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Neuroendocrine regulation and behavior
- Zebrafish Biomedical Research Applications
- Ion channel regulation and function
- Pharmacological Effects and Assays
- Protist diversity and phylogeny
- Ion Transport and Channel Regulation
- Congenital Heart Disease Studies
- Genetic factors in colorectal cancer
- Axon Guidance and Neuronal Signaling
- Cancer, Stress, Anesthesia, and Immune Response
- Genomic variations and chromosomal abnormalities
- Pancreatic function and diabetes
University of Tübingen
2019-2025
Universität Ulm
2011-2020
University Children's Hospital Tübingen
2020
Duke University
2007-2011
Duke Medical Center
2007-2011
Duke University Hospital
2008-2011
University of Freiburg
2007-2008
University of Würzburg
2001-2007
University Medical Center
2007
Heidelberg University
2007
In the adrenergic system, release of neurotransmitter norepinephrine from sympathetic nerves is regulated by presynaptic inhibitory alpha2-adrenoceptors, but it unknown whether epinephrine adrenal gland controlled a similar short feedback loop. Using gene-targeted mice we demonstrate that two distinct subtypes alpha2-adrenoceptors control catecholamines (alpha 2A) and medulla 2C). isolated mouse chromaffin cells, alpha2-receptor activation inhibited electrically stimulated increase in cell...
Alpha(2)-adrenoceptors mediate diverse functions of the sympathetic system and are targets for treatment cardiovascular disease, depression, pain, glaucoma, activation during opioid withdrawal. To determine whether alpha(2)-adrenoceptors on adrenergic neurons or nonadrenergic physiological pharmacological responses alpha(2)-agonists, we used dopamine beta-hydroxylase (Dbh) promoter to drive expression alpha(2A)-adrenoceptors exclusively in noradrenergic cells transgenic mice. Dbh-alpha(2A)...
Abstract Background Axons navigate to their future synaptic targets with the help of choice points, intermediate that express axon guidance cues. Once they reach a point, axons need switch response from attraction repulsion in order move on next stage journey. The mechanisms underlying change axonal responsiveness are poorly understood. Commissural become sensitive repulsive activity Slits when cross ventral midline CNS. Responsiveness depends surface expression Robo receptors. In Drosophila...
About 1% of all newborns are affected by congenital heart disease (CHD). Recent findings identify aberrantly functioning cilia as a possible source for CHD. Faulty also prevent the development proper left-right asymmetry and cause heterotaxy, incorrect placement visceral organs. Intriguingly, signaling cascades such mTOR that influence mitochondrial biogenesis affect ciliogenesis, can heterotaxy-like phenotypes in zebrafish. Here, we levels function determinant ciliogenesis heterotaxy. We...
Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 KPTN variants have been associated with autosomal recessive intellectual disability epileptic encephalopathy. We identified bi-allelic KICS2 in eleven affected individuals presenting epilepsy. These partly stability, compromised complex formation, demonstrated a deleterious impact on...
Background The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine. current study was performed elucidate possible interaction with alpha2-adrenoceptors in mice lacking individual subtypes (alpha2-KO). Methods Sedative and cardiovascular responses alpha2-agonist, dexmedetomidine, were determined deficient alpha2-receptor subtypes. Inhibition binding antagonist [3H]RX821002 recombinant alpha2-receptors...
Although G protein-coupled receptor-mediated signaling is one of the best studied biological events, little known about kinetics these processes in intact cells. Experiments with neurons from α2A-adrenergic receptor knockout mice suggested that α2A-receptor subtype inhibits neurotransmitter release higher speed and at action potential frequencies than α2C-adrenergic receptor. Here we investigated whether functional differences between presynaptic α2-adrenergic subtypes are result distinct...
Wnt ligands conduct their functions in canonical signaling by binding to two receptors, the single transmembrane low density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) seven (7TM) Frizzled receptors. Subsequently, phosphorylation of serine/threonine residues within five repeating signature PPPSP motifs on LRP6 is responsible for activation. GSK3beta, a cytosolic kinase downstream effector beta-catenin, was proposed participate such phosphorylation. Here, we report new class...
Smoothened, a heptahelical membrane protein, functions as the transducer of Hedgehog signaling. The kinases that modulate Smoothened have been thoroughly analyzed in flies. However, little is known about how phosphorylation affects vertebrates, mainly, because residues, where phosphorylated are not conserved from Drosophila to vertebrates. Given its molecular architecture, signaling likely be regulated manner analogous G protein–coupled receptors (GPCRs). Previously, it has shown, arrestins...
Abstract The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient protease exhibit DPC-induced stress genome instability, manifesting as premature ageing liver cancer. Here, we provide a body of evidence suggesting that activates the ATR-CHK1 phosphorylation signalling cascade during physiological by proteolysis-dependent eviction CHK1 from replicative chromatin. During this process, proteolyses...
Protein phosphorylation is a critical regulator of signaling in nearly all eukaryotic cellular pathways and dysregulated has been implicated an array diseases. The majority MS-based quantitative studies are currently performed from transformed cell lines because the ability to generate large amounts starting material with incorporated isotopically labeled amino acids during culture. Here we describe general label-free phosphoproteomic strategy capable directly analyzing relatively small...
Nanog is a homeodomain transcription factor associated with the acquisition of pluripotency. Genome analyses lower and higher vertebrates revealed that existence restricted to gnathostomata but absent from agnatha invertebrates. To elucidate function in nonmammalia, we identified Danio rerio ortholog characterized its role gain loss experiments. We found be crucial for survival early zebrafish embryos, because depletion led gastrulation defects subsequent lethality. Mouse overexpression...
The correct asymmetric placement of inner organs is termed situs solitus and determined early during development. Failure in symmetry breaking results conditions ranging from randomized organ arrangement to a complete mirror image, often accompanied by severe congenital heart defects (CHDs). We found that the zebrafish homolog mammalian G protein-coupled receptor kinase 5 (GRK5) employs noncanonical, receptor-independent functions secure breaking. Knockdown GRK5's closest embryos, Grk5l,...
Patients with an inherited inability to synthesize sufficient amounts of cholesterol develop congenital malformations the skull, toes, kidney and heart. As development these structures depends on functional cilia we investigated whether regulates ciliogenesis through inhibition hydroxymethylglutaryl-Coenzyme A reductase (HMG-CoA-R), rate-limiting enzyme in synthesis. HMG-CoA-R is efficiently inhibited by statins, a standard medication for hyperlipidemia. When zebrafish embryos are treated...
The BRCA2 interactor, centrobin, is a centrosomal protein that has been implicated in centriole duplication and microtubule stability. We used genome editing to ablate CNTROB hTERT-RPE1 cells observed an increased frequency of monocentriolar acentriolar cells. Using novel monoclonal antibody, we found centrobin primarily localizes daughter centrioles but also associates with mother upon serum starvation. Strikingly, loss abrogated primary ciliation Ultrastructural analysis nulls revealed...
Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly autism spectrum disorder. ADSLD patients have normal serum levels but exhibit accumulation of dephosphorylated substrates, S-Ado, SAICAr, latter being implicated neurotoxic effects through unknown mechanisms. We examined phenotypic depletion human cells their relation to outcomes. Using specific...
The G protein-coupled receptor (GPCR)-like molecule Smoothened (Smo) undergoes dynamic intracellular trafficking modulated by the microtubule associated kinase GRK2 and recruitment of β-arrestin. Of this trafficking, especially translocation Smo into primary cilia back to cytoplasm is essential for activation Hedgehog (Hh) signaling in vertebrates. complete mechanism bidirectional transport, however, not completely understood. Here we demonstrate that Growth Arrest Specific 8 (Gas8), a...
Mutations in ATR (ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of deficiency has been attributed to its canonical role DNA damage response signalling following replication fork stalling/collapse. Here, we show that regulates cilia-dependent manner can be uncoupled from function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia slightly reduced length but are...