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 Mitochondria dynamics in postmitotic cells drives neurogenesis through Sirtuin-dependent chromatin remodeling

2020 ◽  
Author(s):  
Ryohei Iwata ◽  
Pierre Vanderhaeghen
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Time Window ◽  
Histone Deacetylation ◽  
Sirtuin 1 ◽  
High Temporal Resolution ◽  
Daughter Cells ◽  
Neuronal Fate ◽  
Mitochondria Dynamics

AbstractThe conversion of neural stem cells into neurons is associated with massive remodeling of organelles and chromatin, but whether and how these are linked to control neuronal fate commitment remains unknown. We examined and manipulated mitochondria dynamics with high temporal resolution during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells that retain high levels of mitochondria fission will become neurons, while those destined to self-renew undergo rapid mitochondria fusion. Induction of mitochondria fusion after mitosis redirects daughter cells towards cell self-renewal, but only during a restricted time window, which is doubled in human cortical stem cells with higher self-renewing potential. Mitochondria dynamics drives neurogenesis through modulation of the NAD+ sensor Sirtuin-1, leading to Histone deacetylation and chromatin remodeling necessary for neurogenic conversion. Our data reveal a post-mitotic critical period of neurogenesis, linking mitochondria state with cell fate.

scholarly journals Time-resolved transcriptomics in neural stem cells identifies a v-ATPase/Notch regulatory loop

2018 ◽  
Vol 217 (9) ◽  
pp. 3285-3300 ◽  
Author(s):  
Sebastian Wissel ◽  
Heike Harzer ◽  
François Bonnay ◽  
Thomas R. Burkard ◽  
Ralph A. Neumüller ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Cell Biology ◽  
Transcriptional Profiling ◽  
Nervous System Development ◽  
Time Resolved ◽  
Daughter Cells ◽  
Regulatory Loop

Drosophila melanogaster neural stem cells (neuroblasts [NBs]) divide asymmetrically by differentially segregating protein determinants into their daughter cells. Although the machinery for asymmetric protein segregation is well understood, the events that reprogram one of the two daughter cells toward terminal differentiation are less clear. In this study, we use time-resolved transcriptional profiling to identify the earliest transcriptional differences between the daughter cells on their way toward distinct fates. By screening for coregulated protein complexes, we identify vacuolar-type H+–ATPase (v-ATPase) among the first and most significantly down-regulated complexes in differentiating daughter cells. We show that v-ATPase is essential for NB growth and persistent activity of the Notch signaling pathway. Our data suggest that v-ATPase and Notch form a regulatory loop that acts in multiple stem cell lineages both during nervous system development and in the adult gut. We provide a unique resource for investigating neural stem cell biology and demonstrate that cell fate changes can be induced by transcriptional regulation of basic, cell-essential pathways.

scholarly journals Cytokinetic Abscission Regulation in Neural Stem Cells and Tissue Development

2021 ◽  
Author(s):  
Katrina C. McNeely ◽  
Noelle D. Dwyer
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Cell Polarity ◽  
Cell Biology ◽  
Tissue Growth ◽  
Developmentally Regulated ◽  
Daughter Cells ◽  
Fate Determinants

Abstract Purpose of Review How stem cells balance proliferation with differentiation, giving rise to specific daughter cells during development to build an embryo or tissue, remains an open question. Here, we discuss recent evidence that cytokinetic abscission regulation in stem cells, particularly neural stem cells (NSCs), is part of the answer. Abscission is a multi-step process mediated by the midbody, a microtubule-based structure formed in the intercellular bridge between daughter cells after mitosis. Recent Findings Human mutations and mouse knockouts in abscission genes reveal that subtle disruptions of NSC abscission can cause brain malformations. Experiments in several epithelial systems have shown that midbodies serve as scaffolds for apical junction proteins and are positioned near apical membrane fate determinants. Abscission timing is tightly controlled and developmentally regulated in stem cells, with delayed abscission in early embryos and faster abscission later. Midbody remnants (MBRs) contain over 400 proteins and may influence polarity, fate, and ciliogenesis. Summary As NSCs and other stem cells build tissues, they tightly regulate three aspects of abscission: midbody positioning, duration, and MBR handling. Midbody positioning and remnants establish or maintain cell polarity. MBRs are deposited on the apical membranes of epithelia, can be released or internalized by surrounding cells, and may sequester fate determinants or transfer information between cells. Work in cell lines and simpler systems has shown multiple roles for abscission regulation influencing stem cell polarity, potency, and daughter fates during development. Elucidating how the abscission process influences cell fate and tissue growth is important for our continued understanding of brain development and stem cell biology.

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.

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 The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML

2012 ◽  
Vol 210 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Florian H. Heidel ◽  
Lars Bullinger ◽  
Patricia Arreba-Tutusaus ◽  
Zhu Wang ◽  
Julia Gaebel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Determinant ◽  
Lethal Giant Larvae ◽  
Evolutionarily Conserved ◽  
Human Acute Myeloid Leukemia ◽  
Early Growth Response 1

A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.

The Balance Between Self-Renewal and Differentiation of Human Neural Stem Cells Requires the Amyloid Precursor Protein

2021 ◽  
Author(s):  
Khadijeh Shabani ◽  
Julien Pigeon ◽  
Marwan Benaissa Touil Zariouh ◽  
Tengyuan Liu ◽  
Azadeh Saffarian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Self Renewal ◽  
Human Neural Stem Cells
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