scholarly journals Tumour Suppressor Parafibromin/Hyrax Governs Cell Polarity and Centrosome Assembly in Neural Stem Cells

2021 ◽  
Author(s):  
Qiannan Deng ◽  
Cheng Wang ◽  
Chwee Tat Koe ◽  
Jan Peter Heinen ◽  
Ye Sing Tan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Polarity ◽  
Tumour Suppressor ◽  
New Paradigm ◽  
Microtubule Organizing Center ◽  
Larval Brain ◽  
Centrosomal Protein ◽  
Tumour Formation ◽  
Organizing Center

Neural stem cells (NSCs) divide asymmetrically to balance their self-renewal and differentiation. The imbalance can lead to NSC overgrowth and tumour formation. The function of Parafibromin, a conserved tumour suppressor, in the nervous system is not established. Here, we demonstrate that Drosophila Parafibromin/Hyrax (Hyx) inhibits NSC overgrowth by governing the cell polarity. Hyx is essential for the apicobasal polarity by localizing both apical and basal proteins asymmetrically in NSCs. hyx loss results in the symmetric division of NSCs, leading to the formation of supernumerary NSCs in the larval brain. Human Parafibromin fully rescues NSC overgrowth and cell polarity defects in Drosophila hyx mutant brains. Hyx plays a novel role in maintaining interphase microtubule-organizing center and mitotic spindle formation in NSCs. Hyx is required for the proper localization of a key centrosomal protein Polo and microtubule-binding proteins Msps and D-TACC in dividing NSCs. This study discovers that Hyx has a brain tumour suppressor-like function and maintains NSC polarity by regulating centrosome function and microtubule growth. The new paradigm that Parafibromin orchestrates cell polarity and centrosomal assembly may be relevant to Parafibromin/HRPT2-associated cancers.

scholarly journals Arl2- and Msps-dependent microtubule growth governs asymmetric division

2016 ◽  
Vol 212 (6) ◽  
pp. 661-676 ◽  
Author(s):  
Keng Chen ◽  
Chwee Tat Koe ◽  
Zhanyuan Benny Xing ◽  
Xiaolin Tian ◽  
Fabrizio Rossi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Polarity ◽  
Control Cell ◽  
Asymmetric Division ◽  
New Paradigm ◽  
Self Renewal ◽  
Tubulin Binding ◽  
Microtubule Growth ◽  
Adp Ribosylation Factor

Asymmetric division of neural stem cells is a fundamental strategy to balance their self-renewal and differentiation. It is long thought that microtubules are not essential for cell polarity in asymmetrically dividing Drosophila melanogaster neuroblasts (NBs; neural stem cells). Here, we show that Drosophila ADP ribosylation factor like-2 (Arl2) and Msps, a known microtubule-binding protein, control cell polarity and spindle orientation of NBs. Upon arl2 RNA intereference, Arl2-GDP expression, or arl2 deletions, microtubule abnormalities and asymmetric division defects were observed. Conversely, overactivation of Arl2 leads to microtubule overgrowth and depletion of NBs. Arl2 regulates microtubule growth and asymmetric division through localizing Msps to the centrosomes in NBs. Moreover, Arl2 regulates dynein function and in turn centrosomal localization of D-TACC and Msps. Arl2 physically associates with tubulin cofactors C, D, and E. Arl2 functions together with tubulin-binding cofactor D to control microtubule growth, Msps localization, and NB self-renewal. Therefore, Arl2- and Msps-dependent microtubule growth is a new paradigm regulating asymmetric division of neural stem cells.

scholarly journals Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions

Angiogenesis ◽  
2020 ◽  
Vol 23 (4) ◽  
pp. 567-575
Author(s):  
Danielle B. Buglak ◽  
Erich J. Kushner ◽  
Allison P. Marvin ◽  
Katy L. Davis ◽  
Victoria L. Bautch
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Polarity ◽  
Adherens Junctions ◽  
Cell Junctions ◽  
Microtubule Organizing Center ◽  
Sprouting Angiogenesis ◽  
Organizing Center ◽  
Important Regulator ◽  
Cell Cell

Abstract Proper blood vessel formation requires coordinated changes in endothelial cell polarity and rearrangement of cell–cell junctions to form a functional lumen. One important regulator of cell polarity is the centrosome, which acts as a microtubule organizing center. Excess centrosomes perturb aspects of endothelial cell polarity linked to migration, but whether centrosome number influences apical–basal polarity and cell–cell junctions is unknown. Here, we show that excess centrosomes alter the apical–basal polarity of endothelial cells in angiogenic sprouts and disrupt endothelial cell–cell adherens junctions. Endothelial cells with excess centrosomes had narrower lumens in a 3D sprouting angiogenesis model, and zebrafish intersegmental vessels had reduced perfusion following centrosome overduplication. These results indicate that endothelial cell centrosome number regulates proper lumenization downstream of effects on apical–basal polarity and cell–cell junctions. Endothelial cells with excess centrosomes are prevalent in tumor vessels, suggesting how centrosomes may contribute to tumor vessel dysfunction.

scholarly journals Drosophila neuroblasts as a new model for the study of stem cell self-renewal and tumour formation

2014 ◽  
Vol 34 (4) ◽  
Author(s):  
Song Li ◽  
Hongyan Wang ◽  
Casper Groth
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Daughter Cell ◽  
Asymmetric Cell Division ◽  
Cell Fate Specification ◽  
Larval Brain ◽  
Self Renewal ◽  
Intrinsic Factors ◽  
Tumour Formation

Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumour-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate ACD (asymmetric cell division). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumour formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in ACD in mammalian systems, which may play significant roles in the series of pathogenic events leading to the development of brain cancers.

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 LARG and mDia1 Link Gα12/13 to Cell Polarity and Microtubule Dynamics

2008 ◽  
Vol 19 (1) ◽  
pp. 30-40 ◽  
Author(s):  
Polyxeni Goulimari ◽  
Helga Knieling ◽  
Ulrike Engel ◽  
Robert Grosse
Keyword(s):  
Cell Polarity ◽  
Glycogen Synthase ◽  
Cell Polarization ◽  
Microtubule Dynamics ◽  
Microtubule Organizing Center ◽  
Embryonic Fibroblasts ◽  
Extracellular Signals ◽  
Receptor Signal ◽  
Organizing Center ◽  
G Protein Coupled

Regulation of cell polarity is a process observed in all cells. During directed migration, cells orientate their microtubule cytoskeleton and the microtubule-organizing-center (MTOC), which involves integrins and downstream Cdc42 and glycogen synthase kinase-3β activity. However, the contribution of G protein-coupled receptor signal transduction for MTOC polarity is less well understood. Here, we report that the heterotrimeric Gα12 and Gα13 proteins are necessary for MTOC polarity and microtubule dynamics based on studies using Gα12/13-deficient mouse embryonic fibroblasts. Cell polarization involves the Gα12/13-interacting leukemia-associated RhoGEF (LARG) and the actin-nucleating diaphanous formin mDia1. Interestingly, LARG associates with pericentrin and localizes to the MTOC and along microtubule tracks. We propose that Gα12/13 proteins exert essential functions linking extracellular signals to microtubule dynamics and cell polarity via RhoGEF and formin activity.

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