scholarly journals Coordinated control of self-renewal and differentiation of neural stem cells by Myc and the p19ARF–p53 pathway

2008 ◽  
Vol 183 (7) ◽  
pp. 1243-1257 ◽  
Author(s):  
Motoshi Nagao ◽  
Kenneth Campbell ◽  
Kevin Burns ◽  
Chia-Yi Kuan ◽  
Andreas Trumpp ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Late Stage ◽  
Early Stage ◽  
Dependent Manner ◽  
Self Renewal ◽  
P53 Pathway ◽  
Glial Fate ◽  
Underlying Mechanisms

The modes of proliferation and differentiation of neural stem cells (NSCs) are coordinately controlled during development, but the underlying mechanisms remain largely unknown. In this study, we show that the protooncoprotein Myc and the tumor suppressor p19ARF regulate both NSC self-renewal and their neuronal and glial fate in a developmental stage–dependent manner. Early-stage NSCs have low p19ARF expression and retain a high self-renewal and neurogenic capacity, whereas late-stage NSCs with higher p19ARF expression possess a lower self-renewal capacity and predominantly generate glia. Overexpression of Myc or inactivation of p19ARF reverts the properties of late-stage NSCs to those of early-stage cells. Conversely, inactivation of Myc or forced p19ARF expression attenuates self-renewal and induces precocious gliogenesis through modulation of the responsiveness to gliogenic signals. These actions of p19ARF in NSCs are mainly mediated by p53. We propose that opposing actions of Myc and the p19ARF–p53 pathway have important functions in coordinated developmental control of self-renewal and cell fate choices in NSCs.

scholarly journals Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

2018 ◽  
Author(s):  
Shiekh Tanveer Ahmad ◽  
Alexandra D. Rogers ◽  
Myra J. Chen ◽  
Rajiv Dixit ◽  
Lata Adnani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Lineage Specification ◽  
Self Renewal ◽  
Important Regulator ◽  
Neuronal Lineage ◽  
Glial Lineage ◽  
Ets Factors ◽  
The Brain

ABSTRACTCapicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic’s function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more weakly expressed in stem cells and oligodendroglial lineage cells. Using a new conditionalCicknockout mouse, we show that forebrain-specificCicdeletion increases proliferation and self-renewal of neural stem cells. Furthermore,Cicloss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage selection effects in the developing brain are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal and tumorigenicity. Our results identify Cic is an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3320-3330 ◽  
Author(s):  
Szabolcs Fatrai ◽  
Albertus T. J. Wierenga ◽  
Simon M. G. J. Daenen ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Target Gene ◽  
Start Codon ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Oxygen Conditions ◽  
Underlying Mechanisms

Abstract The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in self-renewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose long-term expansion exclusively on human HSCs, not on progenitors. This was associated with an enhanced cobblestone formation under bone marrow stromal cells of STAT5-transduced HSCs. Hypoxia-induced factor 2α (HIF2α) was identified as a STAT5 target gene in HSCs, and chromatin immunoprecipitation studies revealed STAT5 binding to a site 344 base pairs upstream of the start codon of HIF2α. Lentiviral RNA interference (RNAi)–mediated down-modulation of HIF2α impaired STAT5-induced long-term expansion and HSC frequencies, whereas differentiation was not affected. Glucose uptake was elevated in STAT5-activated HSCs, and several genes associated with glucose metabolism were up-regulated by STAT5 in an HIF2α-dependent manner. Our studies indicate that pathways normally activated under hypoxia might be used by STAT5 under higher oxygen conditions to maintain and/or impose HSC self-renewal properties.

scholarly journals Coordinated control of self-renewal and differentiation of neural stem cells by Myc and the p19ARF–p53 pathway

2009 ◽  
Vol 184 (2) ◽  
pp. 335-335
Author(s):  
Motoshi Nagao ◽  
Kenneth Campbell ◽  
Kevin Burns ◽  
Chia-Yi Kuan ◽  
Andreas Trumpp ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Coordinated Control ◽  
Self Renewal ◽  
P53 Pathway

Mitochondrial dynamics in postmitotic cells regulate neurogenesis

Science ◽  
2020 ◽  
Vol 369 (6505) ◽  
pp. 858-862 ◽  
Author(s):  
Ryohei Iwata ◽  
Pierre Casimir ◽  
Pierre Vanderhaeghen
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Time Window ◽  
Mitochondrial Dynamics ◽  
Human Cells ◽  
Self Renewal ◽  
Cortical Neurogenesis ◽  
Daughter Cells ◽  
Neuronal Fate

The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.

scholarly journals Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

2019 ◽  
Author(s):  
Neale Harrison ◽  
Elizabeth Connolly ◽  
Alicia Gascón Gubieda ◽  
Zidan Yang ◽  
Benjamin Altenhein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Glial Cells ◽  
De Novo ◽  
Transmembrane Protein ◽  
Lineage Tracing ◽  
Epistasis Analysis ◽  
Induced Neural Stem Cell ◽  
Underlying Mechanisms

ABSTRACTSome animals can regenerate their central nervous system (CNS) after injury by inducing de novo neurogenesis: discovering the underlying mechanisms would help promote regeneration in the damaged human CNS. Glial cells could be the source of regenerative neurogenesis, but this is debated. The glia transmembrane protein Neuron-Glia antigen-2 (NG2) may have a key role in sensing injury-induced neuronal signals, however these have not been identified. Here, we used Drosophila genetics to search for functional neuronal partners of the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell fate, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic epistasis analysis and lineage tracing, we demonstrate that Ia-2 functions with Kon to regulate Drosophila insulin-like peptide 6 (Dilp-6) which in turn generates both more glial cells and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for CNS regeneration.

scholarly journals EBF1 is expressed in pericytes and contributes to pericyte cell commitment

2021 ◽  
Author(s):  
Francesca Pagani ◽  
Elisa Tratta ◽  
Patrizia Dell’Era ◽  
Manuela Cominelli ◽  
Pietro Luigi Poliani
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
B Cell ◽  
Cell Fate ◽  
Early Stage ◽  
Cell Lineage ◽  
Cell Maturation ◽  
Cell Commitment

AbstractEarly B-cell factor-1 (EBF1) is a transcription factor with an important role in cell lineage specification and commitment during the early stage of cell maturation. Originally described during B-cell maturation, EBF1 was subsequently identified as a crucial molecule for proper cell fate commitment of mesenchymal stem cells into adipocytes, osteoblasts and muscle cells. In vessels, EBF1 expression and function have never been documented. Our data indicate that EBF1 is highly expressed in peri-endothelial cells in both tumor vessels and in physiological conditions. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS) analysis suggest that EBF1-expressing peri-endothelial cells represent bona fide pericytes and selectively express well-recognized markers employed in the identification of the pericyte phenotype (SMA, PDGFRβ, CD146, NG2). This observation was also confirmed in vitro in human placenta-derived pericytes and in human brain vascular pericytes (HBVP). Of note, in accord with the key role of EBF1 in the cell lineage commitment of mesenchymal stem cells, EBF1-silenced HBVP cells showed a significant reduction in PDGFRβ and CD146, but not CD90, a marker mostly associated with a prominent mesenchymal phenotype. Moreover, the expression levels of VEGF, angiopoietin-1, NG2 and TGF-β, cytokines produced by pericytes during angiogenesis and linked to their differentiation and activation, were also significantly reduced. Overall, the data suggest a functional role of EBF1 in the cell fate commitment toward the pericyte phenotype.

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