A5081678615- Ion channel regulation and function
- Zebrafish Biomedical Research Applications
- Genetic Neurodegenerative Diseases
- Developmental Biology and Gene Regulation
- Congenital heart defects research
- Pancreatic function and diabetes
- Neuroscience and Neuropharmacology Research
- Nicotinic Acetylcholine Receptors Study
- Hippo pathway signaling and YAP/TAZ
- Single-cell and spatial transcriptomics
- Axon Guidance and Neuronal Signaling
- Cardiac electrophysiology and arrhythmias
- TGF-β signaling in diseases
- Neurological disorders and treatments
- Cardiomyopathy and Myosin Studies
- Genetics and Neurodevelopmental Disorders
- Nitric Oxide and Endothelin Effects
- Diabetes and associated disorders
- Autism Spectrum Disorder Research
- Metabolism and Genetic Disorders
- Pain Mechanisms and Treatments
- Neurogenesis and neuroplasticity mechanisms
- Pancreatic and Hepatic Oncology Research
- Neuroscience and Neural Engineering
- RNA Research and Splicing
MRC Laboratory of Molecular Biology
2023-2024
The Francis Crick Institute
2021-2023
Medical Research Council
2023
Heidelberg University
2017-2020
University Medical Centre Mannheim
2017-2020
University Hospital Heidelberg
2017-2020
University of Trento
2018
University of Perugia
2013-2016
Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, rhythm disturbances neurodevelopmental disorders, potentially SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying short QT interval electrocardiogram recordings autism–epilepsy phenotype. Genetic screening identified novel KCNJ2 variant that (i) enhanced...
Extracellular signal-regulated kinase (Erk) signaling dynamics elicit distinct cellular responses in a variety of contexts. The early zebrafish embryo is an ideal model to explore the role Erk vivo, as gradient activated diphosphorylated (P-Erk) induced by fibroblast growth factor (Fgf) at blastula margin. Here, we describe improved Erk-specific biosensor, which term modified translocation reporter (modErk-KTR). We demonstrate utility this biosensor vitro and developing Drosophila embryos....
Abstract The transcriptional effector SMAD4 is a core component of the TGF-β family signaling pathways. However, its role in vertebrate embryo development remains unresolved. To address this, we deleted Smad4 zebrafish and investigated consequences this on by morphogens, BMPs Nodal. We demonstrate that absence Smad4, dorsal/ventral patterning disrupted due to loss BMP signaling. unexpectedly, Nodal maintained, but lacks robustness. This Smad4-independent sufficient for mesoderm...
Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar and dysarthria, may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting jerking muscle contractions associated hyperthermia, severe migraine, relatively short-sleep phenotype. A single...
Specification of the germ layers by Nodal signaling has long been regarded as an archetype how graded morphogens induce different cell fates. However, this deterministic model cannot explain why only a subset cells at early zebrafish embryo margin adopt endodermal fate, whereas their immediate neighbours, experiencing similar environment, become mesoderm. Combining pharmacology, quantitative imaging and single transcriptomics, we demonstrate that sustained establishes bipotential progenitor...
Loss-of-function mutations in the KCNA1(Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance activity of Kv1.1-containing channels offset functional defects caused KCNA1 has been clinically approved. Here, we uncovered niflumic acid (NFA), prescribed...
Precise temporal coordination of signaling processes is pivotal for cellular differentiation during embryonic development. A vast number secreted molecules are produced and released by cells tissues, travel in the extracellular space. Whether they induce a pathway instruct cell fate, however, depends on complex network regulatory mechanisms, which often not well understood. The conserved bilateral left-right asymmetrically formed habenulae zebrafish an excellent model investigating how...
Dihydropteridine reductase (QDPR) catalyzes the recycling of tetrahydrobiopterin (BH4), a cofactor in dopamine, serotonin, and phenylalanine metabolism. QDPR-deficient patients develop neurological symptoms including hypokinesia, truncal hypotonia, intellectual disability seizures. The underlying pathomechanisms are poorly understood. We established zebrafish model for QDPR deficiency analyzed expression as well function all homologues during embryonic development. qdpra is essential...
An autosomal dominant protein aggregate myopathy, characterized by high plasma creatine kinase and calsequestrin-1 (CASQ1) accumulation in skeletal muscle, has been recently associated with a missense mutation CASQ1 gene. The replaces an evolutionarily-conserved aspartic acid glycine at position 244 (p.D244G) of CASQ1, the main sarcoplasmic reticulum (SR) Ca2+ binding storage localized terminal cisternae muscle cells. Here, immunocytochemical analysis myotubes, differentiated from...
Monitoring cycling behaviours of stem and somatic cells in the living animal is a powerful tool to better understand tissue development homeostasis. The tg(anillin:anillin-eGFP) transgenic line carries full-length zebrafish F-actin binding protein Anillin fused eGFP from bacterial artificial chromosome (BAC) containing cis-regulatory sequences. Here we report suitability Anillin-eGFP reporter as direct indicator late embryonic post-embryonic retina. We show that combining...
The human cerebellum has undergone significant evolutionary expansion compared to other species, contributing both motor and cognitive skills. However, the mechanisms underlying this process remain largely unknown as interrogating cerebellar development alongside species date been unfeasible. To address this, we developed a minimally guided organoid protocol that combines unguided neural induction with precise temporal calibration of posteriorizing morphogens. This approach effectively...
ABSTRACT The considerably slow pace of human brain development correlates with an evolutionary increase in size, cell numbers, and expansion neuronal structures, axon tracts undergoing even greater than other domains. However, whether tempo is responsible for these differences magnitude, how, remains to be determined. Here, we used organoids investigate this observed that spend more time growing extend farther compared those mice, independent their tissue environment. Single RNA sequencing...
Abstract Erk signaling dynamics elicit distinct cellular responses in a variety of contexts. The early zebrafish embryo is an ideal model to explore the role vivo , as gradient activated diphosphorylated (P-Erk) induced by Fgf at blastula embryonic margin. Here we describe improved Erk-specific biosensor which term modified Kinase Translocation Reporter (modErk-KTR). We demonstrate utility this vitro and developing Drosophila embryos. Moreover, show that Fgf/Erk dynamic coupled tissue growth...
Abstract Specification of the germ layers by Nodal signaling has long been regarded as an archetype how graded morphogens induce different cell fates. However, this deterministic model cannot explain why only a subset cells at margin early zebrafish embryo adopt endodermal fate, while their immediate neighbours, experiencing similar profiles, become mesoderm. Combining pharmacology, quantitative imaging and single transcriptomics, we demonstrate that sustained establishes bipotential...
Trigeminal ganglion (TG) neurons are functionally and morphologically heterogeneous, the molecular basis of this heterogeneity is still not fully understood. Here we describe experiments showing that a subpopulation expresses delayed-rectifying K(+) current (IDRK) with characteristically high (nanomolar) sensitivity to dihydroquinoline CP339,818 (CP). Although submicromolar CP has previously been shown selectively block Kv1.3 Kv1.4 channels, CP-sensitive IDRK found in TG could be associated...