A5050642431- Neurogenesis and neuroplasticity mechanisms
- Axon Guidance and Neuronal Signaling
- Hedgehog Signaling Pathway Studies
- Genetic Syndromes and Imprinting
- Nerve injury and regeneration
- Genetic and Kidney Cyst Diseases
- MicroRNA in disease regulation
- Zebrafish Biomedical Research Applications
- Signaling Pathways in Disease
- RNA Research and Splicing
- Neuroinflammation and Neurodegeneration Mechanisms
- Circular RNAs in diseases
- Apelin-related biomedical research
- Cancer-related molecular mechanisms research
- Protein Tyrosine Phosphatases
- Neuroscience and Neuropharmacology Research
- RNA modifications and cancer
- Muscle Physiology and Disorders
- Advanced Fluorescence Microscopy Techniques
- Barrier Structure and Function Studies
- Angiogenesis and VEGF in Cancer
University of Edinburgh
2016-2025
Multiple Sclerosis Society
2025
National University of Singapore
2025
Montreal Neurological Institute and Hospital
2010-2020
McGill University
2012-2020
Mott MacDonald (United Kingdom)
2016
Bipar
2013
Medizinische Hochschule Hannover
2012
Hospital for Sick Children
2009-2011
University of Toronto
2009
Blood–brain barrier function is driven by the influence of astrocyte-secreted factors. During neuroinflammatory responses blood–brain compromised resulting in central nervous system damage and exacerbated pathology. Here, we identified endothelial netrin 1 induction as a vascular response to astrocyte-derived sonic hedgehog that promotes autocrine properties during homeostasis increases with inflammation. Netrin supports integrity upregulating junctional protein expression, while knockout...
Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of mutational analysis our multiethnic cohort 83 families (105 cases); 75.9% them their mutations identified including 26 novel changes. Comprehensive phenotyping these patients demonstrate that spectrum clinical features greater than expected overlapped with other...
The mouse monoclonal antibody marketed as anti-adenomatous polyposis coli clone CC1, often referred to is the most commonly used specifically label mature oligodendrocytes without labeling myelin. Previous studies have shown that despite being raised against adenomatous coli, this binds another unknown antigen. We show CC1 Quaking 7, an RNA-binding protein highly up-regulated in myelinating central nervous system. (APC) cell bodies of oligodendrocytes. Despite APC, previous showed (QKI) which
Netrin-1 regulates cell migration and adhesion during the development of nervous system, vasculature, lung, pancreas, muscle, mammary gland. It is also proposed to function as a dependence ligand that inhibits apoptosis; however, studies disagree regarding whether netrin-1 loss-of-function mice exhibit increased death. Furthermore, previously studied gene-trap express netrin-1-β-galactosidase protein chimera with potential for toxic gain-of-function effects, well small amount wild-type...
SUMMARY Myelination facilitates the rapid conduction of action potentials along axons. In central nervous system (CNS), myelinated axons vary over 100-fold in diameter, with speed scaling linearly increasing diameter. Axon diameter and myelination are closely interlinked, axon exerting a strong influence on myelination. Conversely, myelinating Schwann cells peripheral can both positively negatively affect However, whether is regulated by CNS oligodendrocytes less clear. Here, we investigated...
<h3>Background</h3> Bardet–Biedl syndrome is a pleiotropic disorder with 14 BBS genes identified. BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 form complex called the BBSome, which believed to recruit Rab8<sup>GTP</sup> primary cilium promote ciliogenesis. The second group, chaperonin-like proteins BBS6, BBS10, BBS12, have been defined as vertebrate-specific branch of type II chaperonin superfamily. These may play role in regulation BBSome assembly. <h3>Methods results</h3> Using sequence...
Axon diameter influences the conduction properties of myelinated axons, both directly, and indirectly through effects on myelin. However, we have limited understanding mechanisms controlling axon growth in central nervous system, preventing systematic dissection how manipulating affects myelination along individual axons. Here establish zebrafish to study diameter. We find that importin 13b is required for growth, but does not affect cell body size or length. Using neuron-specific ipo13b...
MicroRNAs (miRs) regulate diverse molecular and cellular processes including oligodendrocyte (OL) precursor cell (OPC) proliferation differentiation in rodents. However, the role of miRs human OPCs is poorly understood. To identify that may these humans, we isolated OL-lineage cells from white matter analyzed their miR profile. Using endpoint RT-PCR assays quantitative real-time PCR, demonstrate miR-219, miR-338 miR-17-92 are enriched expressed acutely OLs. In addition, report expression...
Objective Remyelination in multiple sclerosis has been attributed to the presence of oligodendrocyte progenitor cells (OPCs) brain parenchyma. However, precise identity these progenitors is poorly defined. Here, we characterized populations OPCs adult human and examined their myelination capacity profile miRNAs. Comparisons were made with fetal mature oligodendrocytes. Methods We isolated (early-to-mid second trimester) from surgically resected tissues using O4-, A2B5-, MOG-directed...
The guidance cue netrin-1 and its receptor Deleted in Colorectal Cancer play distinct roles during different stages of oligodendrocyte development. A gradient repels migrating precursor cells (OPCs) the embryonic spinal cord by promoting process collapse, but later development increases extension branching. Here we investigate intracellular mechanism that governs this switch response to netrin-1, focus on role GTPase RhoA effector Rho Kinase (ROCK) downstream OPCs maturing oligodendrocytes....
Abstract Introduction: Historical risk factors for tongue cancer include age, chronic exposure to tobacco and alcohol use. Smoking-related has declined due active anti-tobacco campaigns in developed countries, yet the incidence of increased, particularly women patients under a younger age group. This study aims investigate differences genomic processes driving oncogenesis young old with cancer. Methods: We perform laser-capture microdissection on 54 formalin-fixed paraffin-embedded (FFPE)...
Axon diameter varies up to 100-fold between distinct neurons in the central nervous system with larger axons exhibiting proportionally faster conduction velocity. influences myelination, can be dynamically regulated, which might help fine-tune neural circuit function, and is altered several diseases. Despite its importance, mechanisms regulating axon remain poorly understood. This gap understanding due part limitations of fixed tissue analyses, such as electron microscopy, cannot scaled...
Abstract Myelination by oligodendrocytes in the central nervous system is influenced neuronal activity, but molecular mechanisms which this occurs have remained unclear. Here we employed pharmacological, genetic, functional imaging and optogenetic-stimulation approaches zebrafish to assess activity-regulated myelination vivo. Pharmacological inhibition activation of metabotropic glutamate receptor 5 (mGluR5) impaired promoted myelin sheath elongation, respectively, during development,...
Bardet Biedl syndrome is a genetically heterogeneous ciliopathy with fourteen genes currently identified. To date, mutations in BBS7 and TTC8 (BBS8) were reported 4.2% 2.8% of BBS families respectively. We sequenced the coding regions 35 diverse ancestral backgrounds. In addition, role putative modifier on phenotype severity; NXNL1 MGC1203 c.430C>T, was assessed. Genotype-phenotype correlation explored patients identified mutations. Four novel pathogenic changes 2/35 (5.7%). one family two...
Through a genetic screen in zebrafish, we identified mutant with disruption to myelin both the CNS and PNS caused by mutation previously uncharacterized gene, slc12a2b, predicted encode Na+, K+, Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited severe progressive pathology PNS, characterized dysmyelination swelling of periaxonal space at axon-myelin interface. Cell-type-specific loss either neurons or myelinating Schwann cells recapitulated these pathologies. Given that...
Current in vitro models to investigate the consequence of oligodendrocyte-specific loss-of-function mutations on myelination are primarily limited co-culture experiments, which do not accurately recapitulate complex vivo environment. Here, we describe development an model and myelin maintenance oligodendrocyte precursor cells transplanted into organotypic cerebellar slice cultures derived from dysmyelinated shiverer mice. Compared neuron-oligodendrocyte co-cultures, slices more closely mimic...
Paranodal axoglial junctions are critical for maintaining the segregation of axonal domains along myelinated axons; however, proteins required to organize and maintain this structure not fully understood. Netrin-1 its receptor Deleted in Colorectal Cancer (DCC) enriched at paranodes that expressed by neurons oligodendrocytes. To identify specific function DCC oligodendrocytes vivo , we selectively eliminated from mature myelinating using an inducible cre regulated proteolipid protein...
Abstract Myelinating Schwann cells of the peripheral nervous system (PNS) express numerous ion channels and transporters, have capacity to respond neuronal activity. However, it remains unknown how response activity affects nerve formation, health or function in vivo. Through a genetic screen zebrafish, we identified mutant, ue58 , with severe disruption morphology myelin along nerves associated oedema. Molecular analyses indicated that this phenotype was caused by loss previously...
Background: Remyelination in multiple sclerosis has been attributed to oligodendrocyte progenitor cells (OPCs) present brain parenchyma, but the precise identity of such progenitors and molecular mechanisms controlling their differentiation are incompletely defined. Objective: This study addressed whether different subsets OPCs adult human brains examined expression specific miRNAs implicated OPC differentiation. The profile was then compared between from developing brains. Method: We...
ABSTRACT In the mature CNS, netrin-1 is expressed by neurons and oligodendrocytes implicated in stability of axo-oligodendroglial paranodal junctions. Here we report that netrin receptor UNC5B highly enriched at paranodes. We demonstrate paranodes become disorganized following conditional deletion oligodendrocytes, with disruption interface between glial loops detachment from axon. As a result, Caspr1 Kv1.1 disperse along axon, internodes fail to lengthen compact myelin periodicity reduced....
Summary Central nervous system neurons have axons that vary over 100-fold in diameter. This diversity contributes to the regulation of myelination and conduction velocity along axons, which is critical for proper function. Despite this importance, technical challenges limited our understanding mechanisms controlling axon diameter growth, preventing systematic dissection how manipulating affects individual axons. Here, we establish zebrafish as investigate axonal vivo . We identify a role...