A5024234013- Neurogenesis and neuroplasticity mechanisms
- Neuroscience and Neural Engineering
- Nerve injury and regeneration
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- RNA Research and Splicing
- Cellular transport and secretion
- Neuroendocrine regulation and behavior
- Pluripotent Stem Cells Research
- Parkinson's Disease Mechanisms and Treatments
- Advanced Fluorescence Microscopy Techniques
- Adenosine and Purinergic Signaling
- Stress Responses and Cortisol
- Tryptophan and brain disorders
- Immune cells in cancer
- Gut microbiota and health
- MicroRNA in disease regulation
- CRISPR and Genetic Engineering
- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- RNA regulation and disease
- Photoreceptor and optogenetics research
- Circular RNAs in diseases
- Electrowetting and Microfluidic Technologies
Duke-NUS Medical School
2016-2025
SingHealth
2024
National University of Singapore
2012-2023
Singapore Bioimaging Consortium
2021-2022
Signature Research (United States)
2015
Duke University
2014
Duke University Hospital
2014
Duke Medical Center
2014
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2002-2012
National Institute of Mental Health
2007-2012
SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations have been identified small subgroup individuals with autism spectrum disorder (ASD) intellectual disability. also plays key role chromosome 22q13.3 microdeletion syndrome (Phelan–McDermid syndrome), which includes ASD cognitive dysfunction as major clinical features. To evaluate Shank3 vivo , we disrupted isoforms gene mice by deleting exons...
Abstract Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate brain development and neurological diseases. However, the current systems for organoid culture require further improvement reliable production of high-quality organoids. Here, we demonstrate two engineering elements improve culture, (1) extracellular matrix brain-specific cues (2) microfluidic device with periodic flow survival reduce variability A three-dimensional...
Hyperexcitable neurons in brain organoids Individuals with Angelman syndrome experience intellectual disability and seizures throughout their lives. In this condition, ubiquitin-mediated degradation of a key potassium channel is disrupted, allowing for the neuronal excitability network synchronization that leads to seizure. Sun et al. used organoid technology study what happens human mutation ubiquitin ligase implicated syndrome. these vitro models mouse model syndrome, antagonists...
Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization the active terminal, while retraction less ones. The underlying molecular mechanisms remain unknown. We show that activity-dependent conversion pro–brain-derived neurotrophic factor (proBDNF) mature (m)BDNF mediates synaptic competition. Stimulation motoneurons triggers proteolytic proBDNF mBDNF at nerve terminals. In Xenopus nerve–muscle cocultures, in which two innervate...
The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, anchor. MDGAs contribute to the radial migration positioning subset cortical neurons during early neural development. However, continue be expressed in postnatal brain, their functions development remain unknown. Here, we demonstrate that specifically with nanomolar affinity bind neuroligin-2, cell-adhesion molecule inhibitory synapses, but...
Abstract The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks their output genes are less well known. Here, we report germ-free (GF) mice display altered daily oscillation clock gene expression concomitant change the regulators. Mice exposed microbes typically exhibit characterized activities nuclear receptors, some which...
Gamma-aminobutyric acid (GABA)-releasing interneurons play an important modulatory role in the cortex and have been implicated multiple neurological disorders. Patient-derived could provide a foundation for studying pathogenesis of these diseases as well identifying potential therapeutic targets. Here, we identified set genetic factors that robustly induce human pluripotent stem cells (hPSCs) into GABAergic neurons (iGNs) with high efficiency. We demonstrated iGNs express neurochemical...
Abstract Recent studies have demonstrated the generation of midbrain-like organoids (MOs) from human pluripotent stem cells. However, low efficiency MO and relatively immature heterogeneous structures MOs hinder translation these bench to clinic. Here we describe robust with homogeneous distribution midbrain dopaminergic (mDA) neurons. Our contain not only mDA neurons but also other neuronal subtypes as well functional glial cells, including astrocytes oligodendrocytes. Furthermore, our...
We utilized human midbrain-like organoids (hMLOs) generated from pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α-synuclein (α-syn; SNCA) perturbations to investigate genotype-to-phenotype relationships in Parkinson disease, with the particular aim of recapitulating α-syn- Lewy body-related pathologies process neurodegeneration hMLO model.We characterized hMLOs GBA1-/- SNCA overexpressing isogenic embryonic also body-like inclusions GBA1/SNCA dual perturbation...
Abstract Changes in gut microbiota composition have been linked to anxiety behavior rodents. However, the underlying neural circuitry linking and their metabolites remains unknown. Using male C57BL/6J germ-free (GF) mice, not exposed live microbes, increased anxiety-related was observed correlating with a significant increase immediate early c-Fos gene basolateral amygdala (BLA). This phenomenon coincided intrinsic excitability spontaneous synaptic activity of BLA pyramidal neurons...
Postsynaptic cells generate positive and negative signals that retrogradely modulate presynaptic function. At developing neuromuscular synapses, prolonged stimulation of muscle induces sustained synaptic depression. We provide evidence pro–brain-derived neurotrophic factor (BDNF) is a retrograde signal can be converted into by metalloproteases at the junctions. Application pro-BDNF dramatic decrease in efficacy followed retraction terminals, these effects are mediated pan-neurotrophin...
Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein by inhibiting peptidyl transferase 80S ribosomal function. Therefore, de novo has thought be necessary for long-term memory formation. However, it is unclear which mode of translation—gene-specific general/global translation—is actually crucial consolidation...
To address existing limitations in live neuron imaging, we have developed NeuO, a novel cell-permeable fluorescent probe with an unprecedented ability to label and image neurons selectively over other cells the brain. NeuO enables robust imaging isolation vivo vitro across species; its versatility ease of use sets basis for development myriad neuronal targeting applications.
During the development, tight regulation of expansion neural progenitor cells (NPCs) and their differentiation into neurons is crucial for normal cortical formation function. In this study, we demonstrate that microRNA (miR)-128 regulates proliferation NPCs by repressing pericentriolar material 1 (PCM1). Specifically, overexpression miR-128 reduced NPC but promoted both in vivo vitro. contrast, reduction endogenous elicited opposite effects. Overexpression suppressed translation PCM1,...
Internalization of the neurotrophin–Trk receptor complex is critical for many aspects neurotrophin functions. The mechanisms governing internalization process are unknown. Here, we report that neuronal activity facilitates brain-derived neurotrophic factor, TrkB, by potentiating its tyrosine kinase activity. Using three independent approaches, show electric stimulation hippocampal neurons markedly enhances TrkB internalization. Electric also potentiates activity-dependent enhancement and...
Neurotrophins elicit both acute and long-term modulation of synaptic transmission plasticity. Previously, we demonstrated that the requires endocytosis neurotrophin-receptor complex, activation PI3K Akt, mTOR mediated protein synthesis. However, it is unclear whether by neurotrophins depends on synthesis in pre- or post-synaptic cells.Here have developed an inducible translation blocker, which kinase domain R (PKR) fused with bacterial gyrase B (GyrB-PKR), could be dimerized upon treatment a...
Alternative splicing (AS) is an important source of proteome diversity in eukaryotes. However, how this affects protein repertoires at a single-cell level remains open question. Here, we show that many 3′-terminal exons are persistently co-expressed with their alternatives mammalian neurons. In example scenario, cell polarity gene Cdc42, combination polypyrimidine tract-binding, protein-dependent, and constitutive mechanisms ensures halfway switch from the general (E7) to neuron-specific...
Glial cell line-derived neurotrophic factor (GDNF) is known for its potent effect on neuronal survival, but role in the development and function of synapses not well studied. Using <i>Xenopus</i> nerve-muscle co-cultures, we show that GDNF family member neurturin (NRTN) facilitate neuromuscular junction (NMJ). Long-term application significantly increased total length neurites motoneurons. also caused an increase number size synaptic vesicle clustering, as demonstrated by synaptobrevin-GFP...
The ubiquitin–proteasome pathway has been implicated in synaptic development and plasticity. However, mechanisms by which ubiquitination contributes to precise dynamic control of plasticity are poorly understood. We have identified a PDZ domain containing RING finger 3 (PDZRN3) as synapse-associated E3 ubiquitin ligase demonstrated that it regulates the surface expression muscle-specific receptor tyrosine kinase (MuSK), key organizer postsynaptic at mammalian neuromuscular junction. PDZRN3...
Multiple loss-of-function mutations in TRIAD3 (a.k.a. RNF216) have recently been identified patients suffering from Gordon Holmes syndrome (GHS), characterized by cognitive decline, dementia, and movement disorders. TRIAD3A is an E3 ubiquitin ligase that recognizes facilitates the ubiquitination of its target for degradation ubiquitin-proteasome system (UPS). Here, we demonstrate two these missense substitutions (R660C R694C) could not regulate their neuronal target, activity-regulated...