String (Cdc25) regulates stem cell maintenance, proliferation and aging in <i>Drosophila</i> testis

Inaba, Mayu; Yuan, Hebao; Yamashita, Yukiko

doi:10.1242/dev.072579

Cited by 50 publications

(73 citation statements)

References 29 publications

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“…Loss of ptc results in ligand-independent Hh signaling (Ingham et al, 1991;Chen and Struhl, 1996). We counted 44.6±1.2 Zfh1-positive, Eyanegative cells in testes from eyaA3-gal4/+ control males (n=20), consistent with the previously reported 36-50 Zfh1-positive cells per testis (Leatherman and Dinardo, 2010;Inaba et al, 2011). Ptc knockdown causes a statistically significant increase in the number of Zfh1-positive, Eya-negative CySCs to 73.2±3.1 (n=15, P<9.7ϫ10 -8 ) (Fig.…”

Section: Hh Levels Control Cysc Numbersupporting

confidence: 86%

Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis

et al. 2013

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The Drosophila testis harbors two types of stem cells: germ line stem cells (GSCs) and cyst stem cells (CySCs). Both stem cell types share a physical niche called the hub, located at the apical tip of the testis. The niche produces the JAK/STAT ligand Unpaired (Upd) and BMPs to maintain CySCs and GSCs, respectively. However, GSCs also require BMPs produced by CySCs, and as such CySCs are part of the niche for GSCs. Here we describe a role for another secreted ligand, Hedgehog (Hh), produced by niche cells, in the self-renewal of CySCs. Hh signaling cell-autonomously regulates CySC number and maintenance. The Hh and JAK/STAT pathways act independently and non-redundantly in CySC self-renewal. Finally, Hh signaling does not contribute to the niche function of CySCs, as Hh-sustained CySCs are unable to maintain GSCs in the absence of Stat92E. Therefore, the extended niche function of CySCs is solely attributable to JAK/STAT pathway function.

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Section: Hh Levels Control Cysc Numbersupporting

confidence: 86%

Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis

et al. 2013

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“…Loss of CycB or excess of CycA causes increased female GSC loss (Chen et al, 2009;Wang and Lin, 2005), and Cdc25/string is required for male GSC maintenance (Inaba et al, 2011). CycE function is required for FSC maintenance, and 537 RESEARCH ARTICLE Cyclin E and stem cell fate analysis of CycE WX in the FSC lineage showed that FSC loss occurs in the absence of follicle cell proliferation defects (Wang and Kalderon, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Other cell cycle-independent roles of cell cycle regulators As mentioned above, cell cycle regulators, including Cdc25, CycB and CycA have been implicated in GSC maintenance (Chen et al, 2009;Inaba et al, 2011;Wang and Lin, 2005), although it remains unclear whether they control stem cell fate independently of the cell cycle. Yet, cell cycle regulators perhaps function outside of the cell cycle more commonly than previously thought.…”

Section: F36mentioning

confidence: 99%

“…Cystoblasts undergo four rounds of incomplete mitosis to produce 16-cell germline cysts (composed of one oocyte and 15 nurse cells) that are subsequently enveloped by follicle cells derived from FSCs (Ables et al, 2012). Although core cell cycle machinery components, including Cyclin A (CycA) and Cyclin B (CycB) in females and Cdc25 in males, influence GSC maintenance (Chen et al, 2009;Inaba et al, 2011;Wang and Lin, 2005), it is largely unknown how factors that control proliferation of GSCs modulate their self-renewal.…”

Section: Introductionmentioning

confidence: 99%

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Cyclin E controlsDrosophilafemale germline stem cell maintenance independently of its role in proliferation by modulating responsiveness to niche signals

Ables

Drummond‐Barbosa

2013

Development

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SUMMARYStem cells must proliferate while maintaining 'stemness'; however, much remains to be learned about how factors that control the division of stem cells influence their identity. Multiple stem cell types display cell cycles with short G1 phases, thought to minimize susceptibility to differentiation factors. Drosophila female germline stem cells (GSCs) have short G1 and long G2 phases, and dietdependent systemic factors often modulate G2. We previously observed that Cyclin E (CycE), a known G1/S regulator, is atypically expressed in GSCs during G2/M; however, it remained unclear whether CycE has cell cycle-independent roles in GSCs or whether it acts exclusively by modulating the cell cycle. In this study, we detected CycE activity during G2/M, reflecting its altered expression pattern, and showed that CycE and its canonical partner, Cyclin-dependent kinase 2 (Cdk2), are required not only for GSC proliferation, but also for GSC maintenance. In genetic mosaics, CycE-and Cdk2-deficient GSCs are rapidly lost from the niche, remain arrested in a G1-like state, and undergo excessive growth and incomplete differentiation. However, we found that CycE controls GSC maintenance independently of its role in the cell cycle; GSCs harboring specific hypomorphic CycE mutations are not efficiently maintained despite normal proliferation rates. Finally, CycE-deficient GSCs have an impaired response to niche bone morphogenetic protein signals that are required for GSC self-renewal, suggesting that CycE modulates niche-GSC communication. Taken together, these results show unequivocally that the roles of CycE/Cdk2 in GSC division cycle regulation and GSC maintenance are separable, and thus potentially involve distinct sets of phosphorylation targets.

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“…These mutant CySCs proliferated better, generating more labeled cells within the clone, which could persist up to 7 or 14 days without dying but did not differentiate ( We note that CySC clones with a proliferation defect can differentiate, as has been shown for CySC clones lacking string (stg), the Drosophila Cdc25 homolog. In fact, CySCs with impaired proliferation cannot be maintained in the niche (Inaba et al, 2011). Therefore, a proliferation defect cannot account for the lack of differentiation of Tor mutant clones.…”

Section: A948vmentioning

confidence: 99%

Somatic stem cell differentiation is regulated by PI3K/Tor signaling in response to local cues

et al. 2016

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Stem cells reside in niches that provide signals to maintain selfrenewal, and differentiation is viewed as a passive process that depends on loss of access to these signals. Here, we demonstrate that the differentiation of somatic cyst stem cells (CySCs) in the Drosophila testis is actively promoted by PI3K/Tor signaling, as CySCs lacking PI3K/Tor activity cannot differentiate properly. We find that an insulin peptide produced by somatic cells immediately outside of the stem cell niche acts locally to promote somatic differentiation through Insulin-like receptor (InR) activation. These results indicate that there is a local 'differentiation' niche that upregulates PI3K/Tor signaling in the early daughters of CySCs. Finally, we demonstrate that CySCs secrete the Dilp-binding protein ImpL2, the Drosophila homolog of IGFBP7, into the stem cell niche, which blocks InR activation in CySCs. Thus, we show that somatic cell differentiation is controlled by PI3K/Tor signaling downstream of InR and that the local production of positive and negative InR signals regulates the differentiation niche. These results support a model in which leaving the stem cell niche and initiating differentiation are actively induced by signaling.

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String (Cdc25) regulates stem cell maintenance, proliferation and aging in Drosophila testis

Cited by 50 publications

References 29 publications

Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis

Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis

Cyclin E controlsDrosophilafemale germline stem cell maintenance independently of its role in proliferation by modulating responsiveness to niche signals

Somatic stem cell differentiation is regulated by PI3K/Tor signaling in response to local cues

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