The SWH signalling as a key regulator for the maintenance of NSC quiescence in Drosophila melanogaster

Abstract

One of the challenging questions in recent stem cell biology is how stem cell behavior is regulated and how the balance between proliferation and quiescence is regulated, since deregulation of the proliferative capacity can lead to tumour formation or premature depletion of the progenitor pool (Knoblich, 2010; Cheung et al., 2013). To analyse one aspect of this key developmental process I studied the neural stem cells (NSCs) of the fruit fly Drosophila melanogaster. During my PhD work, I have made two important findings. First, the SWH signalling pathway is an important regulator of overall organ size control of the Drosophila CNS during larval developmental stages. The functional analysis of diverse components of the SWH pathway revealed that this signalling module is necessary for the correct maintenance of Drosophila NSC quiescence between embryonic and larval stages of development. Using the RNAi approach, I have identified various intracellular and extracellular regulators and downstream targets of the SWH signalling pathway in NSCs that play important roles in modulating the activity of this pathway during early larval stages. The transcriptional outcome is regulated by the main effector of this pathway, the transcriptional co-activator Yorkie (Yki), whose activity depends on DNA-binding transcription factors, like Teashirt (Tsh) (Goulev et al., 2008; Wu et al., 2008; Peng et al., 2009). The finding that the known Yki interaction partner Tsh (Peng et al., 2009) is differentially expressed in distinct NSCs across the CNS, leads to the hypothesis that Yki regulate the expression of its target genes in a cell type specific manner. The second finding revealed a highly sophisticated niche signalling to be necessary for the correct regulation of NSC quiescence. This microenvironmental signalling requires so called niche glial cells, which form the neurogenic niche in the CNS of Drosophila melanogaster. The processes of these glial cells as well as the NSCs itself express transmembrane proteins Crb and Ed that activate the highly conserved SWH signalling pathway in NSCs to maintain quiescence and suppress inappropriate cell growth and proliferation during this developmental stage. Taken together these data strongly suggest that Drosophila NSCs depend on extrinsic cues from the surrounding stem cell niche to tightly control the balance between proliferation and quiescence. Adding these far-reaching effects of the SWH pathway concerning stem cell biology and organ size control with the fact that this pathway in highly conserved, makes it a promising factor for putative cancer therapies and regenerative medicine. By way of example it was shown that the human homologs of Yki namely YAP/TAZ have the ability to reprogram terminally differentiated cells into their corresponding, tissue-specific stem cell (Panciera et al., 2016). As part of this effort the results of my PhD thesis shed some light on the involvement of the SWH pathway on the regulation of the activity pattern in Drosophila NSCs.