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Cell Cycle. 2016; 15(12): 1525–1526.
Published online 2016 April 8. doi:  10.1080/15384101.2016.1171653
PMCID: PMC4934065

Hippo pathway regulates neural stem cell quiescence

We have recently reported a new role of the conserved Salvador/Warts/Hippo pathway (SWH) in maintaining cellular quiescence in neural stem cells (NSCs) using the fruit fly Drosophila melanogaster.1 In this feature article we describe these results along with unpublished data.

Stem cells contribute to a variety of processes like development, tissue homeostasis or regeneration. They are undifferentiated cells and yet are able to produce differentiating daughter cells while simultaneously retaining their stem cell identity. The proliferation of stem cells needs tight regulation, since deregulation can lead to tumorous growth or loss of the progenitor pool. When proliferation is not required, stem cells usually reside in an inactive state known as cellular quiescence and local or systemic signals induce their reactivation.2 Initially quiescence was considered as a default state, but nowadays it is well established that cells actively acquire and maintain cellular quiescence.

Drosophila serves as a popular model system to tackle all kinds of biological questions in stem cell biology and NSCs have been used to unravel the fundamental mechanisms of e.g. asymmetric cell division or stem cell identity specification.3 Quiescence and reactivation has been studied, but mainly focused on the signals that reactivate NSCs in the larval brain. Here, it was shown that the nutritional status of the organism is directly linked to the activity of NSCs. At the transition from the embryo to the larva, NSCs are quiescent and exhibit a small cell diameter. When the larvae hatches and starts to feed, the liver-like fat body senses the rise of dietary amino acids and releases growth-promoting systemic signals. Two studies elegantly showed that glial cells receive these signals and respond by releasing insulin-like peptides that activate the canonical insulin receptor kinase pathway in NSCs to initiate growth and proliferation.4,5

To understand how quiescence is regulated, we analyzed the growth behavior of NSCs when known growth regulatory pathways are impaired. Testing TGF-ß (e.g., baboon, TGF-ß receptor) and the JAK/STAT pathway (e.g., STAT92E, effector), we could not find alterations in NSC growth. In contrast, elimination of the 2 core kinases of the highly conserved SWH tumor suppressor pathway, hippo and warts, or a series of canonical upstream regulators, induced a dramatic increase in cell size and cell division of NSCs. The main SWH effector is Yorkie (YAP/TAZ in vertebrates), which is inactive and retained in the cytoplasm in quiescent NSCs whereas reactivated or prematurely reactivated NSCs show nuclear and active Yorkie. Loss or gain of function showed that Yorkie is necessary and sufficient for growth and proliferation of NSCs. We were not able to induce quiescence by ectopic warts, neither was the initiation of quiescence impaired in mutants, elucidating an important role in the maintenance but most probably not in the initiation of quiescence.1

Since the nutritional status via glial cells controls the time point of reactivation we wanted to connect this to the SWH activity in NSCs and found that cell-contact inhibition of growth is one of the driving forces to maintain quiescence. Unexpectedly, 2 prominent upstream regulators of the SWH pathway in epithelial tissues, Crumbs and Echinoid, are expressed in a nutrient-dependent way in glial niche cells and in the NSCs. Depletion of these in only the niche glial cells is sufficient to initiate reactivation of NSCs (Fig. 1).1

Figure 1.
The Hippo signaling pathway maintains quiescence in neural stem cells. Left panel – Cell-cell-contact activates the Hippo pathway to repress growth and proliferation – Yorkie is inactive. Right panel – The increase in resources ...

Recent studies indicate that the SWH pathway might play a similar role in vertebrate NSCs. Components of the SWH pathway are expressed in quiescent NSCs, YAP is expressed in SOX2-positive neural progenitor cells and loss of YAP and FAT4 in neural precursors rescues a proliferation defect in a mouse model for the Van Maldergem syndrome. Depleting fat in Drosophila NSCs causes premature reactivation indicating more upstream regulatory inputs. In vertebrates SWH shows cross-regulation with the WNT signaling pathway and WNT is also implicated in NSCs activation in mouse. Since the SWH pathway is a potent tumor suppressor pathway, our findings might be relevant in 2 aspects associated with cancers. First, understanding how Yorkie/YAP is causing proliferation and growth in NSCs might be relevant in cancer variants, in which the activity of YAP is associated with tumorigenic growth. Second, YAP has been implicated in chemoresistance of cancer stem cells that are considered as quiescent stem cells. Thus, elucidating how SWH acts in NSCs might help to understand the occurrence of resistance or to identify and eliminate quiescent cancer stem cells to complement the success of chemotherapy.6

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

References

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[2] Cheung TH, Rando TA. Nat Rev Mol Cell Biol 2013; 14:329-40; PMID:23698583; http://dx.doi.org/10.1038/nrm3591 [PMC free article] [PubMed] [Cross Ref]
[3] Homem CC, Knoblich JA. Development 2012; 139:4297-310; PMID:23132240; http://dx.doi.org/10.1242/dev.080515 [PubMed] [Cross Ref]
[4] Chell JM, Brand AH. Cell 2010; 143:1161-73; PMID:21183078; http://dx.doi.org/10.1016/j.cell.2010.12.007 [PMC free article] [PubMed] [Cross Ref]
[5] Sousa-Nunes R, et al. Nature 2011; 471:508-12; PMID:21346761; http://dx.doi.org/10.1038/nature09867 [PMC free article] [PubMed] [Cross Ref]
[6] Sebio A, Lenz HJ. Clin Cancer Res 2015; 21:5002-7; PMID: 26384319; http://dx.doi.org/10.1158/1078-0432.CCR-15-0411 [PMC free article] [PubMed] [Cross Ref]

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