A5074345717- Genetic Neurodegenerative Diseases
- Microtubule and mitosis dynamics
- Neurogenesis and neuroplasticity mechanisms
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Congenital heart defects research
- Genomic variations and chromosomal abnormalities
- Genetics and Neurodevelopmental Disorders
- Cellular Mechanics and Interactions
- Endoplasmic Reticulum Stress and Disease
- Muscle Physiology and Disorders
- Axon Guidance and Neuronal Signaling
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Autophagy in Disease and Therapy
- Neuroscience and Neuropharmacology Research
- Fetal and Pediatric Neurological Disorders
- Parkinson's Disease Mechanisms and Treatments
- RNA Research and Splicing
- MicroRNA in disease regulation
- Genetic and Kidney Cyst Diseases
- Genomics and Chromatin Dynamics
- Glioma Diagnosis and Treatment
- Circular RNAs in diseases
Université de Strasbourg
2016-2025
Inserm
2011-2025
Institut de génétique et de biologie moléculaire et cellulaire
2016-2025
Fraunhofer Institute for Interfacial Engineering and Biotechnology
2025
Centre National pour la Recherche Scientifique et Technique (CNRST)
2022-2025
Centre National de la Recherche Scientifique
2007-2024
Institut de Biologie Moléculaire et Cellulaire
2024
University of Liège
2006-2016
Institut Curie
2007-2013
A defect in microtubule (MT)-based transport contributes to the neuronal toxicity observed Huntington's disease (HD). Histone deacetylase (HDAC) inhibitors show neuroprotective effects this devastating neurodegenerative disorder. We report here that HDAC inhibitors, including trichostatin (TSA), increase vesicular of brain-derived neurotrophic factor (BDNF) by inhibiting HDAC6, thereby increasing acetylation at lysine 40 α-tubulin. MT vitro and cells causes recruitment molecular motors...
The family of WD40-repeat (WDR) proteins is one the largest in eukaryotes, but little known about their function brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact neuronal morphology when inactivated mice. Remarkably, all seven showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b Wdr89), or absent (Wdr47), revealing common role for connectivity. We focused on poorly studied WDR47 protein sharing structural...
The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. molecular basis these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 miR-124 are expressed in wall where they target components CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription migrating neurons. This pathway underlies promoting...
Abstract Some mutations of the LRRK2 gene underlie autosomal dominant form Parkinson’s disease (PD). The G2019S is a common mutation that accounts for about 2% PD cases. To understand pathophysiology this and its possible developmental implications, we developed an in vitro assay to model with human induced pluripotent stem cells (hiPSCs) reprogrammed from skin fibroblasts patients suffering LRKK2 mutation. We differentiated hiPSCs into neural (NSCs) further dopaminergic neurons. Here show...
Abstract KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants one duplication in individuals with neurodevelopmental disorders associated brain malformations, including corpus callosum agenesis (ACC) microcephaly. demonstrate, vivo, the expression of specifically recapitulates patients’ abnormalities, microcephaly reduced intra- inter-hemispheric connectivity. establish impede neuronal migration through...
ABSTRACT Distal 1q21.1 deletions and duplications are associated with variable phenotypes including autism, head circumference height defects. To elucidate which gene(s) responsible for the duplication/deletion-associated phenotypes, we performed gene manipulation in zebrafish mice. We modeled duplication by overexpressing eight human protein-coding genes zebrafish. found that overexpression of CHD1L only led to macrocephaly increased larval body length, whereas chd1l deletion caused...
Abstract The ADAT2/ADAT3 (ADAT) complex catalyzes the adenosine to inosine modification at wobble position of eukaryotic tRNAs. Mutations in ADAT3, catalytically inactive subunit complex, have been identified patients presenting with severe neurodevelopmental disorders. Yet, physiological function during brain development remains totally unknown. Here, we investigated role cortical development. First, reported 21 disorders carrying biallelic variants ADAT3. Second, used structural,...
Huntington disease (HD) is associated with early psychiatric symptoms including anxiety and depression. Here, we demonstrate that wild-type huntingtin, the protein mutated in HD, modulates anxiety/depression-related behaviors according to its phosphorylation at serines 1181 1201. Genetic phospho-ablation 1201 mouse reduces basal levels of anxiety/depression-like behaviors. We observe reduction phenotypes increased adult hippocampal neurogenesis. By improving attachment molecular motors...
Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria microcephaly. Though is known as member Kinesin-13 family involved regulation microtubule end dynamics through its ATP dependent MT-depolymerase activity, how lead to still largely unknown. Using cellular utero electroporation approaches, we show here disease-causing disrupts projection neuron positioning interneuron...
The protein p27Kip1 plays roles that extend beyond cell-cycle regulation during cerebral cortex development, such as the of neuronal migration and neurite branching via signaling pathways converge on actin microtubule cytoskeletons. Microtubule-dependent transport is essential for maturation neurons establishment connectivity though synapse formation maintenance. Here, we show controls vesicles organelles along axon mice cortical projection in vitro. Moreover, suppression ortholog, dacapo,...
Abstract Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic adenosine-to-inosine catalysed the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring full activity. Yet, catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse provide molecular basis tRNAs deamination ADAT2 as well ADAT3 inactivation loss...
Abstract De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation in-vivo studies, how four these affect development. We show that mutants neuronal positioning, disrupting locomotion new-born neurons but without affecting progenitors’ proliferation. further demonstrate pathogenic are reduced microtubule dynamics...
Abstract The cerebral cortex is one of the most intricate regions brain that requires elaborate cell migration patterns for its development. Experimental observations show projection neurons migrate radially within cortical wall, whereas interneurons along multiple tangential paths to reach developing cortex. Tight regulation processes ensures proper positioning and functional integration specific circuits. Disruption neuronal often leads dysfunction and/or malformation associated with...
Completion of neuronal migration is critical for brain development. Kif21b a plus-end-directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in neurons. Here we report physiological function during radial projection neurons the mouse developing cortex. In vivo analysis live imaging on cultured slices demonstrate regulates glia-guided locomotion newborn independently its motility microtubules. We show directly binds actin cytoskeleton both vitro...
ABSTRACT Interneuron development is a crucial step of brain corticogenesis. When affected it often leads to dysfunctions, such as epilepsy, intellectual disabilities and autism spectrum disorder. Such defects are observed in the DYRK1A -haploinsufficiency syndrome, caused by mutations , commonly associated cortical excitatory/inhibitory imbalance. However, how this imbalance established syndrome remains elusive. Here, using mouse models live imaging, we show that Dyrk1a specifically...