patched Increases Cellular Proliferation and Skews Neutral Drift Among Testis Stem Cells During Niche Competition. Marc Amoyel1*, Benjamin Simons2, Erika Bach1. 1) Biochemistry and Mol Pharmacology, New York University School of Medicine, New York, NY; 2) Department of Physics and The Wellcome Trust/Gurdon Institute, University of Cambridge, Cambridge UK.
Stem cells are critical for tissue regeneration during adulthood. However competing models exist to explain stem cell behaviour. In one model stem cells are eternal and invariantly divide asymmetrically to produce one stem cell and one differentiating offspring. In another, known as neutral drift, stem cell populations as a whole do not change, but their clonal make-up is dynamic, reflecting loss and replacement of individual stem cells. In the Drosophila testis, the niche maintains two stem cell populations, germ-line stem cells (GSCs) and somatic cyst stem cells (CySCs). CySCs require both JAK/STAT and Hedgehog pathway signalling to self-renew. There are ~12-14 GSCs in a wild-type testis, and it is commonly believed that there are twice as many CySCs as GSCs. Here we first established that in a wild-type testis there are ~13 CySCs, defined as Zfh1-positive cells in physical contact with the niche. Thus, unexpectedly, CySCs exist in a 1:1 ratio with GSCs. Second, we followed single neutral clones and showed that CySC clones obey neutral drift dynamics: individual CySCs are lost and replaced by their neighbours. Third, we show that increasing Hh signalling by mutation of patched (ptc) alters clone size distribution, in favour of the mutant clones. ptc mutant clones outcompete wild-type CySCs and GSCs for niche space. This is due to increased proliferation of ptc mutant cells, not altered adhesion, since reduction of the dose of string (stg), required for G2/M progression, suppresses the colonising behaviour of ptc mutant CySCs. Finally, we show that CySC clones mis-expressing cyclin E and stg, which accelerate the rate of mitosis, also out-compete wild-type CySCs and GSCs, as do clonal mis-expression of other proliferative factors - like yorkie. Thus, increased proliferation is necessary and sufficient to cause niche competition in Drosophila. Finally, we identify a key similarity between vertebrate and invertebrate adult stem cells.