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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    • "Bazcentrosome docking is a more specific criteria compared to centrosome orientation: ∼90% of total GSCs had 'oriented' centrosomes, a category that can be further subdivided into GSCs with 'oriented, but not docked' centrosomes (∼20%) and those with 'oriented and docked' centrosomes (∼70%) (Figure 1D). The remaining ∼10% of total GSCs had misoriented centrosomes as reported previously (Figure 1D) (Cheng et al., 2008; Roth et al., 2012; Yuan et al., 2012). "
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    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. Here, 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.
    eLife Sciences 03/2015; 4(4). DOI:10.7554/eLife.04960 · 9.32 Impact Factor
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    • "Interestingly, loss of Abd-B in larval germline spermatocytes and subsequent loss of PS-Integrin from the neighboring cyst cells is associated with cell non-autonomous effects in the GSCs surrounding the hub: GSC centrosomes are frequently mispositioned and GSC division rates are reduced, which results in a dramatic decline of pre-meiotic cell populations in adult testes. Presumably, the delay in the GSC cell cycle leads to reduced spermatogenesis over the larval, pupal and adult stages and to the accumulation of defects normally observed in aged testes (Boyle et al., 2007; Cheng et al., 2008; Wang and Jones, 2011). In most stem cell systems including Drosophila, aging is associated with progressive loss of stem cell number and activity, leading to compromised tissue function and regeneration (Wang and Jones, 2011). "
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    ABSTRACT: A fundamental question in biology is how complex structures are maintained after their initial specification. We address this question by reviewing the role of the Hox gene Abd-B in Drosophila testis organogenesis, which proceeds through embryonic, larval and pupal stages to reach maturation in adult stages. The data presented in this review highlight a cell- and stage-specific function of Abd-B, since the mechanisms regulating stem cell niche positioning and architecture at different stages seem to be different despite the employment of similar factors. In addition to its described role in the male embryonic gonads, sustained activity of Abd-B in the pre-meiotic germline spermatocytes during larval stages is required to maintain the architecture of the stem cell niche by regulating βPS-Integrin localization in the neighboring somatic cyst cells. Loss of Abd-B is associated with cell non-autonomous effects within the niche, leading to a dramatic reduction of pre-meiotic cell populations in adult testes. Identification of Abd-B target genes revealed that Abd-B mediates its effects by controlling the activity of the Sevenless ligand Boss via its direct targets Src42A and Sec63. During adult stages, when testis morphogenesis is completed with the addition of the acto-myosin sheath originating from the genital disc, stem cell niche positioning and integrity is regulated by Abd-B activity in the acto-myosin sheath whereas Integrin acts in an Abd-B independent way. It seems that the occurrence of new cell types and cell interactions in the course of testis organogenesis made it necessary to adapt the system to the new cellular conditions by reusing the same players for testis stem cell niche positioning in an alternative manner.
    Computational and Structural Biotechnology Journal 01/2015; 4. DOI:10.1016/j.csbj.2015.01.001
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    • "GSCs give rise to gonialblasts, which undergo four rounds of mitosis with incomplete cytokinesis to form clusters of spermatogonia, whereas CySCs give rise to postmitotic cyst cells, which envelop dividing germ cells and sustain their development. GSCs lost through damage or aging are typically replaced by remaining GSCs but can also arise from dedifferentiation of spermatogonia (Brawley and Matunis, 2004; Cheng et al., 2008; Sheng et al., 2009). How lost CySCs are replaced, however, is not understood. "
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    ABSTRACT: Adult stem cells reside in specialized regulatory microenvironments, or niches, where local signals ensure stem cell maintenance. The Drosophila testis contains a well-characterized niche wherein signals from postmitotic hub cells promote maintenance of adjacent germline stem cells and somatic cyst stem cells (CySCs). Hub cells were considered to be terminally differentiated; here, we show that they can give rise to CySCs. Genetic ablation of CySCs triggers hub cells to transiently exit quiescence, delaminate from the hub, and convert into functional CySCs. Ectopic Cyclin D-Cdk4 expression in hub cells is also sufficient to trigger their conversion into CySCs. In both cases, this conversion causes the formation of multiple ectopic niches over time. Therefore, our work provides a model for understanding how oncogenic mutations in quiescent niche cells could promote loss of quiescence, changes in cell fate, and aberrant niche expansion.
    Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.03.058 · 8.36 Impact Factor
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