Centrosome misorientation reduces stem cell division during ageing. Nature

Department of Biomedical Engineering, Center for Ultrafast Optical Science, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nature (Impact Factor: 41.46). 11/2008; 456(7222):599-604. DOI: 10.1038/nature07386
Source: PubMed


Asymmetric division of adult stem cells generates one self-renewing stem cell and one differentiating cell, thereby maintaining tissue homeostasis. A decline in stem cell function has been proposed to contribute to tissue ageing, although the underlying mechanism is poorly understood. Here we show that changes in the stem cell orientation with respect to the niche during ageing contribute to the decline in spermatogenesis in the male germ line of Drosophila. Throughout the cell cycle, centrosomes in germline stem cells (GSCs) are oriented within their niche and this ensures asymmetric division. We found that GSCs containing misoriented centrosomes accumulate with age and that these GSCs are arrested or delayed in the cell cycle. The cell cycle arrest is transient, and GSCs appear to re-enter the cell cycle on correction of centrosome orientation. On the basis of these findings, we propose that cell cycle arrest associated with centrosome misorientation functions as a mechanism to ensure asymmetric stem cell division, and that the inability of stem cells to maintain correct orientation during ageing contributes to the decline in spermatogenesis. We also show that some of the misoriented GSCs probably originate from dedifferentiation of spermatogonia.

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    • "Immunofluorescence staining protocol was used as described previously [11] . The primary antibodies used were: mouse anti-fasciclin III [1:80; obtained from the Developmental Studies Hybridoma Bank (DSHB)], mouse anti-γ-tubulin monoclonal (1:80; GTU-88; Sigma), mouse anti-Adducin-like monoclonal (1:100, obtained from DSHB), goat-anti-Vasa polyclonal (1:80; dc-13; Santa Cruz Biotechnology). "
    [Show abstract] [Hide abstract] ABSTRACT: Stem cells have remarkable self-renewal ability and differentiation potency, which are critical for tissue repair and tissue homeostasis. Recently it has been found, in many systems (e.g. gut, neurons, and hematopoietic stem cells), that the self-renewal and differentiation balance is maintained when the stem cells divide asymmetrically. Drosophila male germline stem cells (GSCs), one of the best characterized model systems with well-defined stem cell niches, were reported to divide asymmetrically, where centrosome plays an important role. Utilizing time-lapse live cell imaging, customized tracking, and image processing programs, we found that most acentrosomal GSCs have the spectrosomes reposition from the basal end (wild type) to the apical end close to hub-GSC interface (acentrosomal GSCs). In addition, these apically positioned spectrosomes were mostly stationary while the basally positioned spectrosomes were mobile. For acentrosomal GSCs, their mitotic spindles were still highly oriented and divided asymmetrically with longer mitosis duration, resulting in asymmetric divisions. Moreover, when the spectrosome was knocked out, the centrosomes velocity decreased and centrosomes located closer to hub-GSC interface. We propose that in male GSCs, the spectrosome recruited to the apical end plays a complimentary role in ensuring proper spindle orientation when centrosome function is compromised.
    Full-text · Article · Apr 2015 · PLoS ONE
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    • "Immunofluorescence staining was performed as described previously (Cheng et al., 2008). The following primary antibodies were used: mouse anti-γ-tubulin (1:100; GTU-88, Sigma-Aldrich, St. Louis, MO), mouse anti-Fasciclin III (FasIII; 1:20; developed by C Goodman and obtained from the Developmental Studies Hybridoma Bank [DSHB], Iowa City, IA), rabbit anti-Thr3-phosphorylated histone H3 (1:200; Cell Signaling Technology, Danvers, MA), rabbit anti-Vasa (1:100; Santa Cruz Biotechnology, Santa Cruz, CA), rat anti-Vasa (1:20; developed by AC Spradling and D Williams and obtained from DSHB), mouse anti-c-myc (1:100; clone 9E10, DSHB), rabbit anti-c-myc (1:30; c3956; Sigma-Aldrich, St. Louis, MO), rabbit anti-Spd-2 (Giansanti et al., 2008) (a kind gift from Maurizio Gatti, Dipartimento di Biologia e Biotecnologie UniversitàUniversit`Università di Roma), guinea pig anti-Baz (1:500; from Cheng-Yu Lee [University of Michigan] and Chris Doe [University of Oregon] ), and rabbit anti- Baz-pS151 and Baz-pS1085 (Krahn et al., 2009) (a kind gift from Andreas Wodarz [Georg-AugustUniversitat Gottingen]). "
    [Show abstract] [Hide abstract] ABSTRACT: Many stem cells divide asymmetrically in order to balance self-renewal with differentiation. The essence of asymmetric cell division (ACD) is the polarization of cells and subsequent division, leading to unequal compartmentalization of cellular/extracellular components that confer distinct cell fates to daughter cells. Because precocious cell division before establishing cell polarity would lead to failure in ACD, these two processes must be tightly coupled; however, the underlying mechanism is poorly understood. In Drosophila male germline stem cells, ACD is prepared by stereotypical centrosome positioning. The centrosome orientation checkpoint (COC) further serves to ensure ACD by preventing mitosis upon centrosome misorientation. In this study, we show that Bazooka (Baz) provides a platform for the correct centrosome orientation and that Baz-centrosome association is the key event that is monitored by the COC. Our work provides a foundation for understanding how the correct cell polarity may be recognized by the cell to ensure productive ACD.
    Full-text · Article · Mar 2015 · eLife Sciences
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    • "Drosophila male GSCs have a SPOC-like mechanism, called the centrosome orientation checkpoint (COC), for delaying the onset of mitosis if centrosomes happen to be incorrectly oriented to the hub cell (Cheng et al., 2008 ). The COC likely acts by altering the localization of Cyclin via the Par-1 kinase which is an AMPK-like kinase as Kin4 ( Cheng et al., 2008). The main difference between SPOC and COC is the timing of cell cycle progression arrest. "
    [Show abstract] [Hide abstract] ABSTRACT: Reproduction and natural selection are the key elements of life. In order to reproduce, the genetic material must be doubled, separated and placed into two new daughter cells, each containing a complete set of chromosomes and organelles. In mitosis, transition from one process to the next is guided by intricate surveillance mechanisms, known as the mitotic checkpoints. Dis-regulation of cell division through checkpoint malfunction can lead to developmental defects and contribute to the development or progression of tumors. This review approaches two important mitotic checkpoints, the spindle assembly checkpoint (SAC) and the spindle position checkpoint (SPOC). The highly conserved spindle assembly checkpoint (SAC) controls the onset of anaphase by preventing premature segregation of the sister chromatids of the duplicated genome, to the spindle poles. In contrast, the spindle position checkpoint (SPOC), in the budding yeast S. cerevisiae, ensures that during asymmetric cell division mitotic exit does not occur until the spindle is properly aligned with the cell polarity axis. Although there are no known homologs, there is indication that functionally similar checkpoints exist also in animal cells. This review can be regarded as an "executable model", which could be easily translated into various quantitative concrete models like Petri nets, ODEs, PDEs, or stochastic particle simulations. It can also function as a base for developing quantitative models explaining the interplay of the various components and proteins controlling mitosis. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · Progress in Biophysics and Molecular Biology
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