A5102860251- Genetics and Neurodevelopmental Disorders
- RNA modifications and cancer
- Axon Guidance and Neuronal Signaling
- Parathyroid Disorders and Treatments
- RNA Research and Splicing
- Hippo pathway signaling and YAP/TAZ
- Neuroscience and Neuropharmacology Research
- Kruppel-like factors research
- Advanced Electron Microscopy Techniques and Applications
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- CRISPR and Genetic Engineering
- Neuroinflammation and Neurodegeneration Mechanisms
- Epigenetics and DNA Methylation
- Dialysis and Renal Disease Management
- MicroRNA in disease regulation
- RNA and protein synthesis mechanisms
- Zebrafish Biomedical Research Applications
- Muscle and Compartmental Disorders
- Genetic Syndromes and Imprinting
- Cell Adhesion Molecules Research
- Signaling Pathways in Disease
- Connective Tissue Growth Factor Research
- Cancer-related molecular mechanisms research
- Endoplasmic Reticulum Stress and Disease
Charité - Universitätsmedizin Berlin
2013-2025
Humboldt-Universität zu Berlin
2018-2024
Freie Universität Berlin
2016-2024
Institute of Cell Biology and Neurobiology
2021
Berlin-Brandenburger Centrum für Regenerative Therapien
2014-2016
Leibniz Institute of Virology (LIV)
2009
Protein synthesis must be finely tuned in the developing nervous system as final essential step of gene expression. This study investigates architecture ribosomes from neocortex during neurogenesis, revealing Ebp1 a high-occupancy 60S peptide tunnel exit (TE) factor protein at near-atomic resolution by cryoelectron microscopy (cryo-EM). Ribosome profiling demonstrated Ebp1-60S binding is highest start codon initiation and N-terminal elongation, regulating ribosome occupancy these codons....
The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as determinant cortical neuron identity. We find specific upregulation synthesis in the progenitors later-born neurons show that translation rates concomitantly half-lives are inherent features subtypes. small molecule screening, identify Ire1α regulator Satb2 neuronal...
Abstract SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as mitotic chromosome associated protein. depletion leads to centrosome detachment from the spindle poles and misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays 21 families bi-allelic variants in detected exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction larval head size concomitant apoptosis likely altered cell cycle...
Neurological conditions are the leading cause of ill health worldwide. Here, we show that neurodevelopmental disorder-associated ubiquitin ligase UBE3C regulates cellular composition murine cerebral cortex and human brain organoids, with its loss favoring neurogenesis suppressing glial fate. Using genetic complementation, demonstrate disease-associated mutations alter autoubiquitination activity disrupt cortical lamination. Proteomic profiling UBE3C-deficient forebrains organoids identifies...
Introduction Obliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast in response to SSc-microenvironment defining growth factors determined responsible mechanisms. Methods studied responses multipotent...
Vascular regeneration depends on intact function of progenitors vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal (MSC). Deregulated MSC differentiation maladaptive cell fate programs associated with age metabolic diseases may exacerbate arteriosclerosis due to excessive transformation osteoblast-like calcifying cells. Targeting mTOR, a central controller fates, could offer novel therapeutic perspectives. In culture model for osteoblastic...
In this study, we characterize the molecular and functional features of a novel protein called SPOC1. SPOC1 RNA expression was previously reported to be highest in highly proliferating tissues increased subset ovarian carcinoma patients, which statistically correlated with poor prognosis residual disease. These observations implied that might play role cellular proliferation oncogenesis. Here show endogenous is labile, primarily chromatin associated its as well localization are regulated...
Abstract Severe vascular calcification develops almost invariably in chronic kidney patients posing a substantial risk to quality of life and survival. This unmet medical need demands identification novel therapeutic modalities. We aimed pinpoint components the uremic microenvironment triggering differentiation progenitors calcifying osteoblast-like cells. In an unbiased approach, assessing individual potency 63 retention solutes enhance calcific phenotype conversion progenitor cells,...
Abstract Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations SATB2 cause Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, craniofacial defects. Here we show controls neuronal migration callosal axonal...
Abnormal development of corpus callosum is relatively common and causes a broad spectrum cognitive impairments in humans. We use acallosal Neurod2/6-deficient mice to study callosal axon guidance within the ipsilateral cerebral cortex. Initial tracts form but fail traverse cingulum are not attracted towards midline absence Neurod2/6. show that restoration Ephrin-A4 (EfnA4) expression embryonic neocortex embryos sufficient partially rescue targeted growth midline. EfnA4 cannot directly...
SUMMARY Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations SATB2 cause Associated Syndrome (SAS), a multisymptomatic syndrome involving intellectual disability, speech delay, epilepsy craniofacial defects. We show controls neuronal migration axonal outgrowth inducing the...
Zeb2 controls neocortex structure by regulating migration onset and neuronal orientation via Nrp1 Cdh6 adhesive pathways.
SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as mitotic chromosome associated protein. depletion leads to centrosome detachment from the spindle poles and misalignment. Aided by gene matching platforms, we 24 individuals with neurodevelopmental delays 18 families bi-allelic variants in detected exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction larval head size concomitant apoptosis likely altered cell cycle progression. In vivo...
SUMMARY Evolutionary expansion of the neocortex is associated with increase in upper layer neurons. Here, we present Inositol-Requiring Enzyme 1α, Ire1α, as an essential determinant fate, neuronal polarization and cortical lamination. We demonstrate a non-canonical function Ire1α regulation global translation rates developing through its dynamic interaction ribosome eIF4A1 eEF-2 expression. Inactivation engenders lower protein synthesis stalled ribosomes decreased number start sites. show...
ABSTRACT Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly and characteristic dysmorphisms. Biallelic mutations of UBE3B , encoding for ubiquitin ligase E3B are causative KOS. In this report, we characterize neuronal functions its murine ortholog Ube3b . We show that regulates dendritic branching in cell-autonomous manner. Moreover, knockout (KO) neurons exhibit increased density...
SUMMARY Protein synthesis must be finely tuned in the nervous system, as it represents an essential feature of neurodevelopmental gene expression, and dominant pathology neurological disease. However, architecture ribosomal complexes developing mammalian brain has not been analyzed at high resolution. This study investigates ribosomes ex vivo from embryonic perinatal mouse neocortex, revealing Ebp1 a 60S peptide tunnel exit binding factor near-atomic resolution by multiparticle cryo-electron...
Introduction: A central role for mTOR in translating the microenvironmental signals to cell differentiation responses is emerging. We reasoned that pharmacologic targeting may confer protection from arteriosclerosis by enhancing regenerative capacity of circulating bone marrow derived mesenchymal stem cells (MSC). Methods: treated human MSC under calcifying conditions with growth factors (GF) implicated adverse arterial remodeling (CTGF, b-FGF, FGF-23, PDGF-BB, TGF-β1) or without Rapa....
Mortality of patients with end-stage renal disease tremendously exceeds that the general population due to excess cardiovascular morbidity. Large middle-sized molecules (LMM) including pro-inflammatory cytokines are major drivers uremic toxicity and cannot be removed sufficiently by conventional high-flux (HFL) hemodialysis. We tested ability plasma from 19 hemodialysis participating in a trial comparing HFL high cut-off (HCO) membranes facilitating removal LMM induce calcification...
Objective Accelerated calcifying arteriosclerosis features osteoblastic transformation of vascular smooth muscle cells (VSMCs) and their progenitors - mesenchymal stromal (MSCs). Targeting signaling pathways controlling cell differentiation could shift maladaptive fate programs towards protective prevent from calcification. mTOR kinase contained in two functionally structurally distinct multiprotein complexes mTORC1 mTORC2 integrates extracellular stimuli into growth responses. We...