Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts

Development ◽  
2002 ◽  
Vol 129 (20) ◽  
pp. 4843-4853 ◽  
Author(s):  
Qin Shen ◽  
Weimin Zhong ◽  
Yuh Nung Jan ◽  
Sally Temple
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Progenitor Cells ◽  
Cortical Development ◽  
Cell Fates ◽  
Unequal Distribution ◽  
Asymmetric Cell Divisions ◽  
Neural Lineage ◽  
Cell Divisions ◽  
Β Tubulin

Stem cells and neuroblasts derived from mouse embryos undergo repeated asymmetric cell divisions, generating neural lineage trees similar to those of invertebrates. In Drosophila, unequal distribution of Numb protein during mitosis produces asymmetric cell divisions and consequently diverse neural cell fates. We investigated whether a mouse homologue m-numb had a similar role during mouse cortical development. Progenitor cells isolated from the embryonic mouse cortex were followed as they underwent their next cell division in vitro. Numb distribution was predominantly asymmetric during asymmetric cell divisions yielding a β-tubulin III− progenitor and a β-tubulin III+ neuronal cell (P/N divisions) and predominantly symmetric during divisions producing two neurons (N/N divisions). Cells from the numb knockout mouse underwent significantly fewer asymmetric P/N divisions compared to wild type, indicating a causal role for Numb. When progenitor cells derived from early (E10) cortex undergo P/N divisions, both daughters express the progenitor marker Nestin, indicating their immature state, and Numb segregates into the P or N daughter with similar frequency. In contrast, when progenitor cells derived from later E13 cortex (during active neurogenesis in vivo) undergo P/N divisions they produce a Nestin+ progenitor and a Nestin– neuronal daughter, and Numb segregates preferentially into the neuronal daughter. Thus during mouse cortical neurogenesis, as in Drosophila neurogenesis, asymmetric segregation of Numb could inhibit Notch activity in one daughter to induce neuronal differentiation. At terminal divisions generating two neurons, Numb was symmetrically distributed in approximately 80% of pairs and asymmetrically in 20%. We found a significant association between Numb distribution and morphology: most sisters of neuron pairs with symmetric Numb were similar and most with asymmetric Numb were different. Developing cortical neurons with Numb had longer processes than those without. Numb is expressed by neuroblasts and stem cells and can be asymmetrically segregated by both. These data indicate Numb has an important role in generating asymmetric cell divisions and diverse cell fates during mouse cortical development.

scholarly journals Emerging mechanisms of asymmetric stem cell division

2018 ◽  
Vol 217 (11) ◽  
pp. 3785-3795 ◽  
Author(s):  
Zsolt G. Venkei ◽  
Yukiko M. Yamashita
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Asymmetric Cell Division ◽  
Binary Outcomes ◽  
Cellular Mechanisms ◽  
Asymmetric Cell Divisions ◽  
Cell Divisions ◽  
Dividing Cells ◽  
Stem Cell Division

The asymmetric cell division of stem cells, which produces one stem cell and one differentiating cell, has emerged as a mechanism to balance stem cell self-renewal and differentiation. Elaborate cellular mechanisms that orchestrate the processes required for asymmetric cell divisions are often shared between stem cells and other asymmetrically dividing cells. During asymmetric cell division, cells must establish asymmetry/polarity, which is guided by varying degrees of intrinsic versus extrinsic cues, and use intracellular machineries to divide in a desired orientation in the context of the asymmetry/polarity. Recent studies have expanded our knowledge on the mechanisms of asymmetric cell divisions, revealing the previously unappreciated complexity in setting up the cellular and/or environmental asymmetry, ensuring binary outcomes of the fate determination. In this review, we summarize recent progress in understanding the mechanisms and regulations of asymmetric stem cell division.

scholarly journals Visualization of individual cell division history in complex tissues

2020 ◽  
Author(s):  
Annina Denoth-Lippuner ◽  
Baptiste N. Jaeger ◽  
Tong Liang ◽  
Stefanie E. Chie ◽  
Lars N. Royall ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Progenitor Cells ◽  
Individual Cell ◽  
Cell Divisions ◽  
Mouse Tissues ◽  
Single Cell Rna Sequencing ◽  
Neural Stem Progenitor Cells

SummaryThe division potential of individual stem cells and the molecular consequences of successive rounds of proliferation remain largely unknown. We developed an inducible cell division counter (iCOUNT) that reports cell division events in human and mouse tissues in vitro and in vivo. Analysing cell division histories of neural stem/progenitor cells (NSPCs) in the developing and adult brain, we show that iCOUNT allows for novel insights into stem cell behaviour. Further, we used single cell RNA-sequencing (scRNA-seq) of iCOUNT-labelled NSPCs and their progenies from the developing mouse cortex and forebrain-regionalized human organoids to identify molecular pathways that are commonly regulated between mouse and human cells, depending on individual cell division histories. Thus, we developed a novel tool to characterize the molecular consequences of repeated cell divisions of stem cells that allows an analysis of the cellular principles underlying tissue formation, homeostasis, and repair.HighlightsiCOUNT reports previous cell divisions in mouse and human cells in vitroiCOUNT detects cell division biographies in complex mouse tissues in vivoiCOUNT allows for the analysis of human neural stem/progenitor cells in human forebrain organoidsSingle cell RNA-sequencing of iCOUNT cells derived from the mouse developing cortex and human forebrain organoids identifies molecular consequences of previous rounds of cell divisionsGraphical abstract

Probing the Mitotic History and Developmental Stage of Hematopoietic Cells Using Single Telomere Length Analysis (STELA)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2449-2449
Author(s):  
Mark Hills ◽  
Kai Lucke ◽  
Connie J. Eaves ◽  
Peter M. Lansdorp
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cord Blood ◽  
Telomere Length ◽  
Progenitor Cells ◽  
Hematopoietic Cells ◽  
Cell Divisions ◽  
Stem And Progenitor Cells ◽  
History Of ◽  
Length Analysis

Abstract In most somatic cells, telomeres shorten with each round of cell division. As a result telomere length can be used to assess the mitotic history of cells with some important caveats: the telomere length at birth is highly variable (presumably reflecting different alleles of genes regulating telomere length in the germline), telomere losses can be compensated by telomerase and the overall decline in telomere length includes sporadic, variable losses of telomere repeats resulting from damage to telomeric DNA and/or replication errors. The first caveat can be circumvented by testing cells from the same individual and sporadic telomere losses can be analyzed by single telomere length analysis (STELA). It is more difficult to exclude the effect of telomerase on telomere length but we have previously shown that, despite readily detectable expression of telomerase, hematopoietic stem and progenitor cells show a progressive decline in telomere length with cell division and with age. The clinical relevance of telomere shortening is illustrated in several recent studies linking very short telomeres to bone marrow failure and pulmonary fibrosis. We now show that purified human hematopoietic populations from mobilized peripheral blood (MPB) and cord blood (CB) enriched for stem cells (Lin−CD34+CD38−Rho−) and successively more mature cells display progressively shorter telomeres, pointing to the utility of this method for studies of the mitotic relationship between various stem and progenitor cells. Ultra-short telomeres were readily observed (and found to be significantly more frequent) in terminally differentiated cell populations of MPB, suggesting that sporadic telomere losses occur more frequently during differentiation. When 1000 Lin−CD34+CD38−Rho− cord blood cells were transplanted into two immuno-deficient mice, the most primitive human hematopoietic cells with a CD34+CD38− phenotype lost 3970 and 2790 bp respectively following regeneration in vivo, indicative of ~ 30–80 cell divisions assuming a telomere loss of 50–100 bp/division. Further losses in more differentiated cells were similar to those observed in cells before transplantation. These results illustrate the power of STELA for analysis of telomeres in rare cells and point to a novel strategy to study the turnover and replicative history of cells. Furthermore, these data demonstrate that self-renewal divisions in stem cells rather than additional cell divisions in downstream progenitors are the primary cause of telomere loss following transplantation.

discordia mutations specifically misorient asymmetric cell divisions during development of the maize leaf epidermis

Development ◽  
1999 ◽  
Vol 126 (20) ◽  
pp. 4623-4633 ◽  
Author(s):  
K. Gallagher ◽  
L.G. Smith
Keyword(s):  
Cell Division ◽  
Preprophase Band ◽  
Cytochalasin D ◽  
Leaf Epidermis ◽  
Asymmetric Cell Divisions ◽  
Maize Leaf ◽  
Cell Divisions ◽  
Cytoskeletal Structure ◽  
Dividing Cells ◽  
Preprophase Bands

In plant cells, cytokinesis depends on a cytoskeletal structure called a phragmoplast, which directs the formation of a new cell wall between daughter nuclei after mitosis. The orientation of cell division depends on guidance of the phragmoplast during cytokinesis to a cortical site marked throughout prophase by another cytoskeletal structure called a preprophase band. Asymmetrically dividing cells become polarized and form asymmetric preprophase bands prior to mitosis; phragmoplasts are subsequently guided to these asymmetric cortical sites to form daughter cells of different shapes and/or sizes. Here we describe two new recessive mutations, discordia1 (dcd1) and discordia2 (dcd2), which disrupt the spatial regulation of cytokinesis during asymmetric cell divisions. Both mutations disrupt four classes of asymmetric cell divisions during the development of the maize leaf epidermis, without affecting the symmetric divisions through which most epidermal cells arise. The effects of dcd mutations on asymmetric cell division can be mimicked by cytochalasin D treatment, and divisions affected by dcd1 are hypersensitive to the effects of cytochalasin D. Analysis of actin and microtubule organization in these mutants showed no effect of either mutation on cell polarity, or on formation and localization of preprophase bands and spindles. In mutant cells, phragmoplasts in asymmetrically dividing cells are structurally normal and are initiated in the correct location, but often fail to move to the position formerly occupied by the preprophase band. We propose that dcd mutations disrupt an actin-dependent process necessary for the guidance of phragmoplasts during cytokinesis in asymmetrically dividing cells.

Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽  
2021 ◽  
Author(s):  
Dirk Loeffler ◽  
Florin Schneiter ◽  
Weijia Wang ◽  
Arne Wehling ◽  
Tobias Kull ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Human Blood ◽  
Asymmetric Cell Division ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

scholarly journals A fern WUSCHEL-RELATED HOMEOBOX gene functions in both gametophyte and sporophyte generations

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Christopher E. Youngstrom ◽  
Lander F. Geadelmann ◽  
Erin E. Irish ◽  
Chi-Lien Cheng
Keyword(s):  
Stem Cells ◽  
Lateral Roots ◽  
Homeobox Gene ◽  
Genetic Networks ◽  
Land Plants ◽  
Seed Plants ◽  
Wild Type ◽  
Cell Fates ◽  
Cell Divisions ◽  
Gene Functions

Abstract Background Post-embryonic growth of land plants originates from meristems. Genetic networks in meristems maintain the stem cells and direct acquisition of cell fates. WUSCHEL-RELATED HOMEOBOX (WOX) transcription factors involved in meristem networks have only been functionally characterized in two evolutionarily distant taxa, mosses and seed plants. This report characterizes a WOX gene in a fern, which is located phylogenetically between the two taxa. Results CrWOXB transcripts were detected in proliferating tissues, including gametophyte and sporophyte meristems of Ceratopteris richardii. In addition, CrWOXB is expressed in archegonia but not the antheridia of gametophytes. Suppression of CrWOXB expression in wild-type RN3 plants by RNAi produced abnormal morphologies of gametophytes and sporophytes. The gametophytes of RNAi lines produced fewer cells, and fewer female gametes compared to wild-type. In the sporophyte generation, RNAi lines produced fewer leaves, pinnae, roots and lateral roots compared to wild-type sporophytes. Conclusions Our results suggest that CrWOXB functions to promote cell divisions and organ development in the gametophyte and sporophyte generations, respectively. CrWOXB is the first intermediate-clade WOX gene shown to function in both generations in land plants.

scholarly journals SEPT7 Interacts with KIF20A and Regulates the Proliferative State of Neural Progenitor Cells During Cortical Development

2019 ◽  
Vol 30 (5) ◽  
pp. 3030-3043 ◽  
Author(s):  
Runxiang Qiu ◽  
Qiu Runxiang ◽  
Anqi Geng ◽  
Jiancheng Liu ◽  
C Wilson Xu ◽  
...  
Keyword(s):  
Cell Division ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Cortical Development ◽  
Neural Progenitor ◽  
Mammalian Brain ◽  
Additional Cell ◽  
A Cell

Abstract Balanced proliferation and differentiation of neural progenitor cells (NPCs) are critical for brain development, but how the process is regulated and what components of the cell division machinery is involved are not well understood. Here we report that SEPT7, a cell division regulator originally identified in Saccharomyces cerevisiae, interacts with KIF20A in the intercellular bridge of dividing NPCs and plays an essential role in maintaining the proliferative state of NPCs during cortical development. Knockdown of SEPT7 in NPCs results in displacement of KIF20A from the midbody and early neuronal differentiation. NPC-specific inducible knockout of Sept7 causes early cell cycle exit, precocious neuronal differentiation, and ventriculomegaly in the cortex, but surprisingly does not lead to noticeable cytokinesis defect. Our data uncover an interaction of SEPT7 and KIF20A during NPC divisions and demonstrate a crucial role of SEPT7 in cell fate determination. In addition, this study presents a functional approach for identifying additional cell fate regulators of the mammalian brain.

scholarly journals Temporal and epigenetic regulation of neurodevelopmental plasticity

2007 ◽  
Vol 363 (1489) ◽  
pp. 23-38 ◽  
Author(s):  
Nicholas D Allen
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Developmental Plasticity ◽  
Neural Progenitor Cells ◽  
Embryonic Stem ◽  
Neural Progenitor ◽  
Neural Progenitors ◽  
Developmental Potential ◽  
Neural Lineage

The anticipated therapeutic uses of neural stem cells depend on their ability to retain a certain level of developmental plasticity. In particular, cells must respond to developmental manipulations designed to specify precise neural fates. Studies in vivo and in vitro have shown that the developmental potential of neural progenitor cells changes and becomes progressively restricted with time. For in vitro cultured neural progenitors, it is those derived from embryonic stem cells that exhibit the greatest developmental potential. It is clear that both extrinsic and intrinsic mechanisms determine the developmental potential of neural progenitors and that epigenetic, or chromatin structural, changes regulate and coordinate hierarchical changes in fate-determining gene expression. Here, we review the temporal changes in developmental plasticity of neural progenitor cells and discuss the epigenetic mechanisms that underpin these changes. We propose that understanding the processes of epigenetic programming within the neural lineage is likely to lead to the development of more rationale strategies for cell reprogramming that may be used to expand the developmental potential of otherwise restricted progenitor populations.

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