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WIREs Dev Biol
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Spindle positioning in the stem cell niche

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Abstract Stem cells are the source of differentiated cells that constitute tissues and organs. Two fundamental characteristics of stem cells are their abilities to self‐renew stem cell identity and to produce differentiated cells, the balance of which can be achieved by asymmetric stem cell division. Many stem cells have been shown to reside in a stem cell niche, the home of stem cells that regulates the stem cell behavior. Recent studies have revealed the critical contribution of cytoskeletons in achieving asymmetric stem cell division: mitotic spindles in dividing stem cells are often oriented with respect to the stem cell niche, which is supported by concerted actions of microtubule networks and components at the cell membrane such as adherens junctions, the actin cytoskeleton, and the extracellular matrix. In this article, we review the mechanism of stem cell spindle orientation, with emphasis on its relationship with the stem cell niche, and discuss how it contributes to tissue development and homeostasis. WIREs Dev Biol 2012, 1:215–230. doi: 10.1002/wdev.16 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Aging

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Mechanisms of asymmetric stem cell division. (a) Asymmetric stem cell division by extrinsic fate determinants provided by the stem cell niche. Stem cells divide asymmetrically by orienting the mitotic spindle such that only one daughter remains in the stem cell niche and has access to signals necessary for maintaining stem cell identity. Here, daughter cells that initially have equivalent developmental potential acquire different fates by placement in distinct cellular microenvironments. (b) Asymmetric stem cell division by intrinsic fate determinants. Cell fate determinants are unequally partitioned into the daughter cells, thus leading to daughters with distinct fates. Shown here are the self‐renewing (red) factors inherited by the stem cell/or and differentiation (blue) factors inherited by the differentiating daughter cell.

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Mitotic asymmetries of DNA and protein aggregates. (a) According to the immortal strand model, stem cells asymmetrically segregate newly synthesized bromodeoxyuridine (BrdU)‐positive strands into differentiating daughter cells, such that stem cell retains only the unlabeled older strands. On the other hand, if chromosomes are randomly segregated, then both the stem cell and the differentiating daughter cell randomly inherit the BrdU‐labeled chromosomes until the entire BrdU label is diluted stochastically over time. (b) Aggregates of misfolded proteins accumulate near one of the centrosomes and are asymmetrically inherited during mitosis such that majority of the aggresomes are retained in the short‐lived progeny.

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Asymmetric cell division in mammalian epithelial stem cells. (a) During embryonic development, most cell divisions are symmetric in order to maintain the epithelium as a single layer. (b) During stratification, majority of the cell divisions become asymmetric, such that the mitotic spindle is perpendicular to the basement membrane. Different cell fate determinants are segregated unequally between the stem cell (basal) and differentiated (suprabasal) cell.

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Asymmetric cell division in Drosophila male and female germline and somatic stem cells. (a–c) Male and female germline and somatic stem cells attach to the hub cells by adherens junctions consisting of Drosophila epithelial (DE)‐cadherin and Armadillo. (a) Male germline stem cells (GSCs) always orient their spindle perpendicular to the hub. This stereotypical orientation of mitotic spindle is prepared by the precisely controlled positioning of the centrosomes during interphase. Specifically, the mother centrosome (red) normally remains adjacent to the hub and is inherited by the GSC, where as the daughter centrosome (purple) migrates to the opposite side of the cell and is inherited by the gonialblast (GB). Male GSCs require centrosomin (Cnn) and ademomatous polyposis coli 2 (Apc2) proteins to correctly orient the centrosomes during interphase. (b) In contrast to GSCs, cyst stem cells (CySCs) divide asymmetrically by repositioning their spindle during anaphase. The spindle poles rock back and forth until the onset of anaphase, and then one of the poles moves closer to the hub. CySCs require Cnn, moesin (Moe), and dynein motor proteins for anaphase spindle repositioning. (c) Female GSCs also divide asymmetrically by orienting their spindle by anchoring one of the spindle poles to the spectrosome, which remains close to the hub–GSC interface throughout the cell cycle. Female GSCs require Hts protein (an integral component of the spectrosome/fusome) and cytoplasmic dynein to orient the spindle perpendicular to the hub.

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Drosophila male and female germline and somatic stem cells. (a) At the apical tip of the testis, germline stem cells (GSCs), and cyst stem cells (CySCs) are physically attached to the hub cells via an E‐cadherin‐based adherens junction. GSCs divide asymmetrically where one of the daughters maintains stem cell identity and the other initiates differentiation as a gonialblast (GB) (see also Figure 3). GBs further undergo four synchronous divisions with incomplete cytokinesis, producing clusters of 16 interconnected spermatogonia, which give rise to spermatocytes and ultimately to sperm. A pair of CySCs encapsulates a GSC and provides essential signals for GSC identity. CySCs divide asymmetrically to self‐renew and produce somatic support cells called cyst cells. A pair of cyst cells envelop each GB and its progeny, providing signals mediating differentiation. (b) At the anterior tip of the ovariole, GSCs are attached to the cap cells via adherens junctions. GSCs divide asymmetrically in order to self‐renew as well as to produce a cystoblast (CB) that initiates differentiation (see also Figure 3). CB further divides four times to give rise to 16 germ cell cysts interconnected by the fusome, of which only one ultimately becomes an oocyte while the remaining 15 serve as nurse cells. Escort stem cells (ESCs) encapsulate the GSC, while their daughters, escort cells, encapsulate the differentiating germ cells. (c) Hub cells express unpaired (Upd), which activates STAT in GSCs and CySCs required for stem cell self‐renewal. Male GSCs also require Dpp and Gbb expressed in hub cells and CySCs for self‐renewal. (d) Female GSCs require BMP and Piwi/YB signaling from cap cells for self‐renewal. In addition, GSC self‐renewal also requires Janus kinase–signal transducer and activator of transcription (JAK–STAT) activation in the ESCs, which mediates unknown signaling to GSCs.

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