scholarly journals Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1591 ◽  
Author(s):  
Laura Reiche ◽  
Patrick Küry ◽  
Peter Göttle
Keyword(s):  
Down Syndrome ◽  
White Matter ◽  
Cell Fate ◽  
Neuronal Development ◽  
Demyelinating Diseases ◽  
Therapeutic Interventions ◽  
Cell Lineages ◽  
Cns Malformations ◽  
Current Experience

Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.

scholarly journals Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Han-Chung Lee ◽  
Kai-Leng Tan ◽  
Pike-See Cheah ◽  
King-Hwa Ling
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Cell Fate ◽  
Mouse Models ◽  
Neuronal Cell ◽  
Janus Kinase ◽  
Chromosome 21 ◽  
Severe Intellectual Disability ◽  
Stat Signaling

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

scholarly journals A polycomb-independent role of EZH2 in TGFβ1-damaged epithelium triggers a fibrotic cascade with mesenchymal cells

2020 ◽  
Author(s):  
Huy Quang Le ◽  
Matthew Alexander Hill ◽  
Ines Kollak ◽  
Wioletta Skronska-Wasek ◽  
Victoria Schroeder ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Cell Fate ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Transforming Growth Factor Β1 ◽  
Therapeutic Interventions ◽  
Polycomb Repressive Complex 2 ◽  
Cell Fate Decisions ◽  
Transcriptional Complex

AbstractTo restore organ homeostasis, a myriad of cell types need to activate rapid and transient programs to adjust cell fate decisions and elicit a collective behaviour. Characterisation of such programs are imperative to elucidate an organ’s regenerative capacity and its aberrant repair in disease. By modelling epithelial-mesenchymal crosstalk, we provide direct evidence for transforming growth factor β1 (TGFβ1)-damaged epithelium initiating a bi-directional fibrotic cascade with the mesenchyme. Strikingly, TGFβ1-damaged epithelia facilitates the release of Enhancer of Zester Homolog 2 (EZH2) from Polycomb Repressive Complex 2 (PRC2) to establish a novel fibrotic transcriptional complex of EZH2, RNA-polymerase II (POL2) and nuclear actin. Perturbing this complex by disrupting epithelial EZH2 or actomyosin remodelling abrogates the fibrotic crosstalk. The liberation of EZH2 from PRC2 is accompanied by an EZH2-EZH1 switch to preserve global H3K27me3 occupancy. Our results reveal an important non-canonical function of EZH2, paving the way for therapeutic interventions in fibrotic disease.

The role of cell lineage in development

1985 ◽  
Vol 312 (1153) ◽  
pp. 3-19 ◽  
Keyword(s):  
Cell Fate ◽  
Cell Lineage ◽  
Early Embryo ◽  
Embryonic Cell ◽  
Evolutionary Divergence ◽  
Causative Role ◽  
Embryonic Cells ◽  
Developmental Potential ◽  
Cell Lineages

Studies of the role of cell lineage in development began in the latter part of the 19th century, fell into decline in the early part of the 20th, and were revived about 20 years ago. This recent revival was accompanied by the introduction of new and powerful analytical techniques. Concepts of importance for cell lineage studies include the principal division modes by which a cell may give rise to its descendant clone (proliferative, stem cell and diversifying); developmental determinacy , or indeterminacy , which refer to the degree to which the normal cleavage pattern of the early embryo and the developmental fate of its individual cells is, or is not, the same in specimen after specimen; commitment , which refers to the restriction of the developmental potential of a pluripotent embryonic cell; and equivalence group , which refers to two or more equivalently pluripotent cell clones that normally take on different fates but of which under abnormal conditions one clone can take on the fate of another. Cell lineage can be inferred to have a causative role in developmental cell fate in embryos in which induced changes in cell division patterns lead to changes in cell fate. Moreover, such a causative role of cell lineage is suggested by cases where homologous cell types characteristic of a symmetrical and longitudinally metameric body plan arise via homologous cell lineages. The developmental pathways of commitment to particular cell fates proceed according to a mixed typologic and topographic hierarchy, which appears to reflect an evolutionary compromise between maximizing the ease of ordering the spatial distribution of the determinants of commitment and minimizing the need for migration of differentially committed embryonic cells. Comparison of the developmental cell lineages in leeches and insects indicates that the early course of embryogenesis is radically different in these phyletically related taxa. This evolutionary divergence of the course of early embryogenesis appears to be attributable to an increasing prevalence of polyclonal rather than monoclonal commitment in the phylogenetic line leading from an annelid-like ancestor to insects.

scholarly journals The Role of Amyloid-β in White Matter Damage: Possible Common Pathogenetic Mechanisms in Neurodegenerative and Demyelinating Diseases

2020 ◽  
Vol 78 (1) ◽  
pp. 13-22
Author(s):  
Anna M. Pietroboni ◽  
Annalisa Colombi ◽  
Tiziana Carandini ◽  
Elio Scarpini ◽  
Daniela Galimberti ◽  
...  
Keyword(s):  
White Matter ◽  
Grey Matter ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Demyelinating Diseases ◽  
White Matter Damage ◽  
Lesion Load ◽  
Predictive Role ◽  
Disease Stages

Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer’s disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology.

scholarly journals Sustained ErbB activation causes demyelination and hypomyelination by driving necroptosis of mature oligodendrocytes and apoptosis of oligodendrocyte precursor cells

2020 ◽  
Author(s):  
Xu Hu ◽  
Guanxiu Xiao ◽  
Li He ◽  
Xiaojie Niu ◽  
Huashun Li ◽  
...  
Keyword(s):  
White Matter ◽  
Adolescent Development ◽  
Demyelinating Diseases ◽  
Erbb Receptors ◽  
Synergistic Activation ◽  
Developmental Deficit ◽  
Oligodendrocyte Precursor ◽  
Egf Family ◽  
Induced Apoptosis

AbstractOligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in the CNS myelin integrity are largely unknown. Here we overactivate ErbB receptors that mediate signaling of either neuregulin or EGF family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination prior to these pathological events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By analyzing the differentiation states of cells that were pulse- labeled with a viral reporter, we found that, during juvenile to adolescent development, Plp-tTA targeted mainly mature oligodendrocytes (MOs), while Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA supported the reporter pulse-labeling results, and consolidated their non-overlapping targeting preferences in the oligodendrocyte lineage after early development. These features enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused pathological demyelination, whereas in OPCs induced apoptosis that caused developmental hypomyelination. These results established an upstream pathogenic role of ErbB overactivation in oligodendrocytes, providing molecular and cellular insights into the primary oligodendropathy in demyelinating diseases.

scholarly journals C21orf91 Regulates Oligodendroglial Precursor Cell Fate—A Switch in the Glial Lineage?

2021 ◽  
Vol 15 ◽  
Author(s):  
Laura Reiche ◽  
Peter Göttle ◽  
Lydie Lane ◽  
Paula Duek ◽  
Mina Park ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neuronal Development ◽  
Cognitive Impairments ◽  
Cell Lineage ◽  
Precursor Cell ◽  
Structure And Dynamics ◽  
A Cell ◽  
The Central Nervous System ◽  
Glial Lineage

Neuropathological diseases of the central nervous system (CNS) are frequently associated with impaired differentiation of the oligodendroglial cell lineage and subsequent alterations in white matter structure and dynamics. Down syndrome (DS), or trisomy 21, is the most common genetic cause for cognitive impairments and intellectual disability (ID) and is associated with a reduction in the number of neurons and oligodendrocytes, as well as with hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS and underestimated the role of glial cells as pathogenic players. This also relates to C21ORF91, a protein considered a key modulator of aberrant CNS development in DS. We investigated the role of C21orf91 ortholog in terms of oligodendrogenesis and myelination using database information as well as through cultured primary oligodendroglial precursor cells (OPCs). Upon modulation of C21orf91 gene expression, we found this factor to be important for accurate oligodendroglial differentiation, influencing their capacity to mature and to myelinate axons. Interestingly, C21orf91 overexpression initiates a cell population coexpressing astroglial- and oligodendroglial markers indicating that elevated C21orf91 expression levels induce a gliogenic shift towards the astrocytic lineage reflecting non-equilibrated glial cell populations in DS brains.

scholarly journals Oligodendrocyte ARNT2 expression is altered in models of MS

2020 ◽  
Vol 7 (4) ◽  
pp. e745
Author(s):  
Pierre Becquart ◽  
Jake Johnston ◽  
Carles Vilariño-Güell ◽  
Jacqueline A. Quandt
Keyword(s):  
White Matter ◽  
Neuronal Development ◽  
Primary Cultures ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Autoimmune Encephalomyelitis ◽  
Aryl Hydrocarbon ◽  
Demyelinating Disorders ◽  
Interfering Rna

ObjectiveWe examined expression of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), a basic-loop-helix transcription factor implicated in neuronal development and axonal health, in oligodendrocyte (OL) cultures and over the course of chronic experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS).MethodsWe assessed OL ARNT2 expression in EAE compared with sham-immunized controls and also in OL primary cultures and over the course of dibutyryl cyclic adenosine monophosphate (dbcAMP)-mediated maturation of the immortalized Oli-neu cell line. We also tested the functional role of ARNT2 in influencing OL characteristics using small interfering RNA (siRNA).ResultsARNT2 is localized to Olig2+ cells in healthy spinal cord gray and white matter. Despite a significant expansion of Olig2+ cells in the white matter at peak disease, ARNT2 is reduced by almost half in OLs, along with a reduction in the percentage of ARNT2+/Olig2+ cells. Mature OLs in mixed cortical cultures or OLs matured from embryonic progenitors express negligible ARNT2. Similarly, Oli-neu cells express high levels of ARNT2, which are reduced following dbcAMP maturation. siRNA-mediated knockdown of ARNT2 affected OL viability, which led to an enrichment of myelin-producing OLs.ConclusionThe analysis of ARNT2 expression in OLs demonstrates that OL ARNT2 expression is altered in EAE and during OL maturation. Findings point to ARNT2 as an important mediator of OL viability and differentiation and warrant further characterization as a target for intervention in demyelinating disorders such as MS.

scholarly journals The multi-faceted role of Gata3 in developmental haematopoiesis

Open Biology ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 180152 ◽  
Author(s):  
Nada Zaidan ◽  
Katrin Ottersbach
Keyword(s):  
Cell Fate ◽  
Complex Nature ◽  
Haematopoietic Stem Cells ◽  
Cell Cycle Genes ◽  
Cell Lineages ◽  
Early Embryonic Lethality ◽  
Determining Factors ◽  
Stem And Progenitor Cells ◽  
Cancer Types

The transcription factor Gata3 is crucial for the development of several tissues and cell lineages both during development as well as postnatally. This importance is apparent from the early embryonic lethality following germline Gata3 deletion, with embryos displaying a number of phenotypes, and from the fact that Gata3 has been implicated in several cancer types. It often acts at the level of stem and progenitor cells in which it controls the expression of key lineage-determining factors as well as cell cycle genes, thus being one of the main drivers of cell fate choice and tissue morphogenesis. Gata3 is involved at various stages of haematopoiesis both in the adult as well as during development. This review summarizes the various contributions of Gata3 to haematopoiesis with a particular focus on the emergence of the first haematopoietic stem cells in the embryo—a process that appears to be influenced by Gata3 at various levels, thus highlighting the complex nature of Gata3 action.

scholarly journals Calcium Signaling Regulates Autophagy and Apoptosis

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2125
Author(s):  
Pramod Sukumaran ◽  
Viviane Nascimento Da Conceicao ◽  
Yuyang Sun ◽  
Naseem Ahamad ◽  
Luis R Saraiva ◽  
...  
Keyword(s):  
Cell Survival ◽  
Neuronal Development ◽  
Critical Role ◽  
Therapeutic Interventions ◽  
Cellular Functions ◽  
Excitable Cells ◽  
Modulate Function ◽  
Promote Cell Survival ◽  
Regulatory Aspect

Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca2+ channels and Ca2+ storage in various organelles is critical in maintaining cytosolic Ca2+ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca2+ homeostasis is a store operated Ca2+ entry (SOCE) mechanism that is activated by the depletion of Ca2+ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells. Ca2+ has been shown to regulate opposing functions such as autophagy, that promote cell survival; on the other hand, Ca2+ also regulates programmed cell death processes such as apoptosis. The functional significance of the TRP/Orai channels has been elaborately studied; however, information on how they can modulate opposing functions and modulate function in excitable and non-excitable cells is limited. Importantly, perturbations in SOCE have been implicated in a spectrum of pathological neurodegenerative conditions. The critical role of autophagy machinery in the pathogenesis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, would presumably unveil avenues for plausible therapeutic interventions for these diseases. We thus review the role of SOCE-regulated Ca2+ signaling in modulating these diverse functions in stem cell, immune regulation and neuromodulation.

scholarly journals PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Ashok Arasu ◽  
Sengottuvelan Murugan ◽  
Musthafa Mohamed Essa ◽  
Thirunavukkarasu Velusamy ◽  
Gilles J. Guillemin
Keyword(s):  
Tumor Suppressor ◽  
Cell Fate ◽  
Cancer Progression ◽  
Tumor Suppressor Function ◽  
Aberrant Expression ◽  
Tissue Specific ◽  
Cell Lineages ◽  
Neurodevelopmental Disease ◽  
Potential Link

Metastasis is the most deadly aspect of cancer and results from acquired gene regulation abnormalities in tumor cells. Transcriptional regulation is an essential component of controlling of gene function and its failure could contribute to tumor progression and metastasis. During cancer progression, deregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators, collectively influences multiple steps of the metastasis cascade, including local invasion and dissemination of the tumor to distant organs. Transcription factor PAX3/Pax3, which contributes to diverse cell lineages during embryonic development, plays a major role in tumorigenesis. Mutations in this gene can cause neurodevelopmental disease and the existing literature supports that there is a potential link between aberrant expression of PAX3 genes in adult tissues and a wide variety of cancers. PAX3 function is tissue-specific and could contribute to tumorigenesis either directly as oncogene or as a tumor suppressor by losing its function. In this review, we discuss comprehensively the differential role played by PAX3 in various tissues and how its aberrant expression is implicated in disease development. This review particularly highlights the oncogenic and tumor suppressor role played by PAX3 in different cancers and underlines the importance of precisely identifying tissue-specific role of PAX3 in order to determine its exact role in development of cancer.

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