Specific roles of Target of rapamycin in the control of stem cells and their progeny in the<i>Drosophila</i>ovary

LaFever, Leesa; Feoktistov, Alexander; Hsu, Hwei-Jan; Drummond‐Barbosa, Daniela

doi:10.1242/dev.050351

Cited by 127 publications

(174 citation statements)

References 73 publications

(126 reference statements)

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“…A similar role for stem cell maintenance was observed for Drosophila ovarian GSCs and mammalian hematopoietic stem cells, although the underlying mechanisms could be different (LaFever et al, 2010;Sun et al, 2010). For example, DE-cadherin expression was not altered in Tsc1/2 mutant germline stem cells (Sun et al, 2010), or in Tsc1/2 mutant imaginal disc cells (supplementary material Fig.…”

Section: Tsc1/2-torc1-s6k Signaling Regulates Ee Cell Differentiationmentioning

confidence: 58%

TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation via Rheb-TORC1-S6K but independent of nutrition status or Notch regulation

Quan¹,

Sun²,

Lin³

et al. 2013

Journal of Cell Science

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SummaryTubular sclerosis complex gene products TSC1 and TSC2 have evolutionarily conserved roles in cell growth from Drosophila to mammals. Here we reveal important roles for TSC1/2 in regulating intestinal stem cell (ISC) maintenance and differentiation of the enteroendocrine cell lineage in the Drosophila midgut. Loss of either the Tsc1 or Tsc2 gene in ISCs causes rapid ISC loss through TORC1 hyperactivation, because ISCs can be efficiently rescued by mutation of S6k or by rapamycin treatment. In addition, overexpression of Rheb, which triggers TORC1 activation, recapitulates the phenotype caused by TSC1/2 disruption. Genetic studies suggest that TSC1/2 maintains ISCs independently of nutritional status or Notch regulation, probably by inhibiting cell delamination. We show that Tsc1/Tsc2 mutant ISCs can efficiently produce enterocytes but not enteroendocrine cells, and this altered differentiation potential is also caused by hyperactivation of TORC1. Reduced TORC1-S6K signaling by mutation of S6k, however, has no effect on ISC maintenance or cell lineage differentiation. Our studies demonstrate that hyperactivation of TORC1 following the loss of TSC1/2 is detrimental to stem cell maintenance and multiple lineage differentiation in the Drosophila ISC lineage, a mechanism that could be conserved in other stem cell lineages, including that in humans.

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Section: Tsc1/2-torc1-s6k Signaling Regulates Ee Cell Differentiationmentioning

confidence: 58%

TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation via Rheb-TORC1-S6K but independent of nutrition status or Notch regulation

Quan¹,

Sun²,

Lin³

et al. 2013

Journal of Cell Science

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“…Interestingly, Tor has recently been shown to also have insulin-independent roles in germline stem cell proliferation in the Drosophila ovary. 13 We expected that disruption of the insulin signaling pathway would lead to degenerating egg chambers, resembling those seen in starved WT flies. Surprisingly, we found many abnormal Pwop egg chambers in which the NCs persisted and the FCs disappeared, indicating that PCD was initiated but incomplete.…”

Section: Discussionmentioning

confidence: 99%

“…7 InR, chico, Akt, Tor, and S6k GLCs have a growth delay in which they produce only early stage egg chambers, indicating that insulin signaling is required to progress into mid oogenesis. 7,13 Because insulin signaling mutant egg chambers arrest before entering mid oogenesis, the early stages may be incompatible for the induction of PCD. DIAP1 levels remain high in early stage WT egg chambers but are reduced in mid-stage egg chambers, likely making them more vulnerable to starvation-induced PCD.…”

Section: Discussionmentioning

confidence: 99%

“…The insulin signaling pathway is involved in the regulation of apoptosis and autophagic PCD at several points during Drosophila development. 11,12 In the Drosophila ovary, insulin signaling is important for germline stem cell division, 7,13 but evidence that it is involved in the regulation of PCD in mid oogenesis is limited. The insulin receptor (InR) and the InR substrate (Chico) are required for egg chamber progression and proliferation of FCs; 5,7 however, the phenotype of the terminal egg chambers has not been closely analyzed.…”

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confidence: 99%

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Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Pritchett

McCall

2012

Cell Death Differ

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Amino-acid starvation leads to an inhibition of cellular proliferation and the induction of programmed cell death (PCD) in the Drosophila ovary. Disruption of insulin signaling has been shown to inhibit the progression of oogenesis, but it is unclear whether this phenotype mimics starvation. Here, we investigate whether the insulin-mediated phosphoinositide kinase-3 pathway regulates PCD in mid oogenesis. We reasoned that under well-fed conditions, disruption of positive components of the insulin signaling pathway within the germline would mimic starvation and produce degenerating egg chambers. Surprisingly, mutants did not mimic starvation but instead produced many abnormal egg chambers in which the somatic follicle cells disappeared and the germline persisted. These abnormal egg chambers did not show an induction of caspases and lysosomes like that observed in wild-type (WT) degenerating egg chambers. Egg chambers from insulin signaling mutants were resistant to starvation-induced PCD, indicating that a complete block in insulin-signaling prevents the proper response to starvation. However, target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. These results suggest that inhibition of the insulin signaling pathway is not sufficient to regulate starvation-induced PCD in mid oogenesis. Furthermore, starvation-induced PCD is regulated by Tor signaling converging with the canonical insulin signaling pathway. The insulin-mediated class I phosphoinositide kinase-3 (PI3K) pathway is a highly conserved nutrient-sensing pathway in diverse organisms. In mammals, insulin signaling affects oocyte maturation and fertilization. 1,2 Mutations in the insulin signaling pathway in C. elegans can lengthen life span but reduce fertility. 3,4 Improper insulin signaling in Drosophila leads to reduced body size and female sterility. 5 Thus, insulin signaling is essential for reproduction in diverse organisms, but how this pathway regulates fertility is not fully understood.Proper nutrition during Drosophila oogenesis is critical for egg chamber production. 6-8 Depriving flies of yeast as a protein source leads to programmed cell death (PCD) at two stages: early oogenesis in the germarium and mid oogenesis during stages 7-9. 7 Egg chambers undergoing PCD during mid oogenesis are characterized by nuclear condensation and fragmentation of germline-derived nurse cells (NCs), engulfment by somatic follicle cells (FCs), and ultimately FC death. 5 During PCD in mid oogenesis, dying NCs show characteristics of both apoptotic and autophagic PCD. 5 The effector caspase Death caspase-1 (Dcp-1) is essential for germline PCD in mid oogenesis. dcp-1 mutants that have been starved display mid-stage egg chambers that have a persistence of uncondensed NC nuclei but an absence of FCs. 5 This phenotype indicates that the dcp-1 mutant germline is unable to die in response to starvation, although the FCs respond and undergo PCD. dcp-1 mutants ...

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“…The honeybee TOR pathway plays a key role in the development of queen bees, 34) the sole fertile individuals in the bee caste. 21) Moreover, it has been reported that TOR is required for the proliferation, growth, and survival of differentiating germ cells, 35) while germline stem cells and follicle stem cells in Drosophila ovaries have been found to respond to diet via IIS. 36) Taken together, these findings suggest that Egfr-mediated signaling and the subsequent control of fecundity through ovary maturation is mediated not only by RJ and royalactin, but also by FDRJ.…”

Section: )mentioning

confidence: 99%

Freeze-Dried Royal Jelly Maintains Its Developmental and Physiological Bioactivity inDrosophila melanogaster

Kayashima

Yamanashi

Sato

et al. 2012

Bioscience, Biotechnology, and Biochemistry

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Specific roles of Target of rapamycin in the control of stem cells and their progeny in theDrosophilaovary

Cited by 127 publications

References 73 publications

TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation via Rheb-TORC1-S6K but independent of nutrition status or Notch regulation

TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation via Rheb-TORC1-S6K but independent of nutrition status or Notch regulation

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Freeze-Dried Royal Jelly Maintains Its Developmental and Physiological Bioactivity inDrosophila melanogaster

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