Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

Stine, Rachel R.; Greenspan, Leah J.; Ramachandran, Kapil; Matunis, Erika

doi:10.1371/journal.pgen.1004713

Cited by 49 publications

(57 citation statements)

References 84 publications

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“…Recently, it was shown that, yet again, Abl kinase functions downstream of SlitRobo in this context and inhibits E-Cadherin (Shotgun)-mediated adhesion (Stine et al, 2014). Interestingly, activation of JAK-STAT chemokine signaling can induce robo2 expression in this system.…”

Section: Slit-robo Signaling In Organogenesismentioning

confidence: 99%

Slit-Robo signaling

2016

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Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation.

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Section: Slit-robo Signaling In Organogenesismentioning

confidence: 99%

Slit-Robo signaling

2016

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“…CySCs require JAK/STAT signaling for self-renewal, and the hub produces the JAK/STAT pathway ligand Unpaired (Upd) to maintain CySCs (Kiger et al, 2001;Leatherman and Dinardo, 2008;Tulina and Matunis, 2001). Additionally, CySCs require Hedgehog, Hippo, Slit/Robo and MAPK signals in order to remain at the niche and compete for space (Amoyel et al, 2013(Amoyel et al, , 2014(Amoyel et al, , 2016Issigonis et al, 2009;Michel et al, 2012;Stine et al, 2014). In addition to intercellular signaling, many autonomous factors maintain CySCs, particularly the transcription factor Zfh1, which marks the CySC population (Leatherman and Dinardo, 2008).…”

Section: Introductionmentioning

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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“…Activated STAT leads to the transcriptional up-regulation of genes within the stem cells that are important for their maintenance, while differentiating cells are located away from the hub and presumably receive less of the Upd signal. GSCs and CySCs require JAK and its downstream target STAT to prevent their differentiation (Flaherty et al, 2010; Hombría and Brown, 2002; Kiger et al, 2001; Leatherman and Dinardo, 2008; Ma et al, 2014; Stine et al, 2014; Tulina and Matunis, 2001). However, whether niche signals promote stem cell viability in this tissue has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Niche signaling promotes stem cell survival in the Drosophila testis via the JAK–STAT target DIAP1

Hasan

Hétié

Matunis

2015

Developmental Biology

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Tissue-specific stem cells are thought to resist environmental insults better than their differentiating progeny, but this resistance varies from one tissue to another, and the underlying mechanisms are not well-understood. Here, we use the Drosophila testis as a model system to study the regulation of cell death within an intact niche. This niche contains sperm-producing germline stem cells (GSCs) and accompanying somatic cyst stem cells (or CySCs). Although many signals are known to promote stem cell self-renewal in this tissue, including the highly conserved JAK-STAT pathway, the response of these stem cells to potential death-inducing signals, and factors promoting stem cell survival, have not been characterized. Here we find that both GSCs and CySCs resist cell death better than their differentiating progeny, under normal laboratory conditions and in response to potential death-inducing stimuli such as irradiation or starvation. To ask what might be promoting stem cell survival, we characterized the role of the anti-apoptotic gene Drosophila inhibitor of apoptosis 1 (diap1) in testis stem cells. DIAP1 protein is enriched in the GSCs and CySCs and is a Jak-STAT target. diap1 is necessary for survival of both GSCs and CySCs, and ectopic up-regulation of DIAP1 in somatic cyst cells is sufficient to non-autonomously rescue stress-induced cell death in adjacent differentiating germ cells (spermatogonia). Altogether, our results show that niche signals can promote stem cell survival by up-regulation of highly conserved anti-apoptotic proteins, and suggest that this strategy may underlie the ability of stem cells to resist death more generally.

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Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

Cited by 49 publications

References 84 publications

Slit-Robo signaling

Slit-Robo signaling

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

Niche signaling promotes stem cell survival in the Drosophila testis via the JAK–STAT target DIAP1

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