Met is required for oligodendrocyte progenitor cell migration in Danio rerio.
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ABSTRACT:
SUBMITTER: Ali MF
PROVIDER: S-EPMC8473979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Invadolysin is an essential, conserved metalloprotease which links cell division with cell migration and is intriguingly associated with lipid droplets. In this work we examine the expression pattern, protein localisation and gross anatomical consequences of depleting invadolysin in the teleost Danio rerio. We observe that invadolysin plays a significant role in cell migration during development. When invadolysin is depleted by targeted morpholino injection, the appropriate deposition of neuromast clusters and distribution of melanophores are both disrupted. We also observe that blood vessels generated via angiogenesis are affected in invadolysin morphant fish while those formed by vasculogenesis appear normal, demonstrating an unanticipated role for invadolysin in vessel formation. Our results thus highlight a common feature shared by, and a requirement for invadolysin in, these distinct morphological events dependent on cell migration.
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Project description:BackgroundAs a global environmental concern, hypoxia is known to be associated with many biological and physiological impairments in aquatic ecosystems. Previous studies have mainly focused on the effect of hypoxia in adult animals. However, the effect of hypoxia and the underlying mechanism of how hypoxia affects embryonic development of aquatic animals remain unclear.Methodology/principal findingsIn the current study, the effect of hypoxia on primordial germ cell (PGC) migration in zebrafish embryos was investigated. Hypoxic embryos showed PGC migration defect as indicated by the presence of mis-migrated ectopic PGCs. Insulin-like growth factor (IGF) signaling is required for embryonic germ line development. Using real-time PCR, we found that the mRNA expression levels of insulin-like growth factor binding protein (IGFBP-1), an inhibitor of IGF bioactivity, were significantly increased in hypoxic embryos. Morpholino knockdown of IGFBP-1 rescued the PGC migration defect phenotype in hypoxic embryos, suggesting the role of IGFBP-1 in inducing PGC mis-migration.Conclusions/significanceThis study provides novel evidence that hypoxia disrupts PGC migration during embryonic development in fish. IGF signaling is shown to be one of the possible mechanisms for the causal link between hypoxia and PGC migration. We propose that hypoxia causes PGC migration defect by inhibiting IGF signaling through the induction of IGFBP-1.
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Project description:RNA-sequencing of cells collected from 72 hpf embryos: Schwann cells (Gt(foxd3:mCherry);Tg(sox10:mEGFP)), oligodendrocyte lineage cells (Tg(olig2:dsred);Tg(sox10:megfp)), and neurons (Tg(nbt:dsred))
2021-05-15 | GSE174486 | GEO
Project description:Recruitment of oligodendrocyte precursor cells (OPCs) to the lesions is the most important event for remyelination after central nervous system (CNS) injury or in demyelinating diseases. However, the underlying molecular mechanism is not fully understood. In the present study, we found high concentrations of ATP could increase the number of migrating OPCs in vitro, while after pretreatment with oxidized ATP (a P2X7 receptor antagonist), the promotive effect was attenuated. The promotive effect of 2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) (a P2X7 receptor agonist) was more potent than ATP. After incubation with BzATP, the activity of Fyn, one member of the Src family of kinases, was enhanced. Moreover, the interaction between P2X7 and Fyn was identified by co-immunoprecipitation. After blocking the activity of Fyn or down-regulating the expression of Fyn, the migration of OPCs induced by BzATP was inhibited. These data indicate that P2X7 receptors/Fyn may mediate ATP-induced OPC migration under pathological conditions.
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Project description:BackgroundPromotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs. It is also unknown whether astrocytes or microglia play a functional role in IgM-mediated lesion repair.MethodsWe assessed the effect of rHIgM22 on cell proliferation in mixed CNS glial and OPC cultures by tritiated-thymidine uptake and by double-label immunocytochemistry using the proliferation marker, Ki-67. Antibody-mediated signaling events, OPC differentiation and OPC survival were investigated and quantified by Western blots.ResultsrHIgM22 stimulates OPC proliferation in mixed glial cultures but not in purified OPCs. There is no proliferative response in astrocytes or microglia. rHIgM22 activates PDGFαR in OPCs in mixed glial cultures. Blocking PDGFR-kinase inhibits rHIgM22-mediated OPC proliferation in mixed glia. We confirm in isolated OPCs that rHIgM22-mediated anti-apoptotic signaling and inhibition of OPC differentiation requires PDGF and FGF-2. We observed no IgM-mediated effect in mature OLs in the absence of PDGF and FGF-2.ConclusionStimulation of OPC proliferation by rHIgM22 depends on co-stimulatory astrocytic and/or microglial factors. We demonstrate that rHIgM22-mediated activation of PDGFαR is required for stimulation of OPC proliferation. We propose that rHIgM22 lowers the PDGF threshold required for OPC proliferation and protection, which can result in remyelination of CNS lesions.
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Project description:Hypoxia in newborns tends to result in developmental deficiencies in the white matter of the brain. As previous studies of the effects of hypoxia on neuronal development in rodents and human infants have been unable to use in vivo imaging, insight into the dynamic development of oligodendrocytes (OLs) in the central nervous system under hypoxia is limited. Here, we developed a visual model to study OL development using sublethal postnatal hypoxia in zebrafish larvae. We observed that hypoxia significantly suppressed OL progenitor cell migration toward the dorsum using in vivo imaging. Further, we found that hypoxia affected myelination, as indicated by thinner myelin sheaths and by a downregulation of myelin basic protein expression. Bmp2b protein expression was also significantly downregulated following hypoxia onset. Using gain of function and loss of function experiments, we demonstrated that the Bmp2b protein was associated with the regulation of OL development. Thus, our work provides a visual hypoxia model within which to observe OL development in vivo, and reveals the underlying mechanisms involved in these processes.
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Project description:The most challenging aspect of secondary progressive multiple sclerosis (SPMS) is the lack of efficient regenerative response for remyelination, which is carried out by the endogenous population of adult oligoprogenitor cells (OPCs) after proper activation. OPCs must proliferate and migrate to the lesion and then differentiate into mature oligodendrocytes. To investigate the OPC cellular component in SPMS, we developed induced pluripotent stem cells (iPSCs) from SPMS-affected donors and age-matched controls (CT). We confirmed their efficient and similar OPC differentiation capacity, although we reported SPMS-OPCs were transcriptionally distinguishable from their CT counterparts. Analysis of OPC-generated conditioned media (CM) also evinced differences in protein secretion. We further confirmed SPMS-OPC CM presented a deficient capacity to stimulate OPC in vitro migration that can be compensated by exogenous addition of specific components. Our results provide an SPMS-OPC cellular model and encouraging venues to study potential cell communication deficiencies in the progressive form of multiple sclerosis (MS) for future treatment strategies.
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