Molecular Mechanisms behind Germline Stem Cell Parasitism
Cell competition (CC) is a universal, quality control process found across the taxonomic spectrum in which neighboring or interacting cells compare their relative fitness (e.g., growth rates.) In this process the “winner” cells contribute to the further development of the organism or tissue, while suboptimal cells, or “losers,” are outcompeted. This process has been studied in organisms ranging from fungi to humans, and has both developmental and disease relevance. For example, during cancer development, neoplastic cells can function as super-competitors in a tissue, outcompeting wild-type cells and driving tumor growth.
Although there is intense interest, the molecular mechanisms that underlie this process are not well understood. One potential candidate pathway shown to be involved in tumorigenesis is the Notch Pathway. Recent studies have shown that differentially elevated expression of the Notch ligand Jagged is associated with heightened invasiveness and motility of cancer cells as well as increased tumor development. Here we utilize a novel in vivo system that allows us to study individual stem cells during a migration and niche lodgment process. The unique biology of the colonial tunicate, Botryllus schlosseri, has germline stem cells (GSCs) with genetically determined competitive phenotypes; when GSCs of two individuals are mixed, one genotype will outcompete the other, solely contributing to the germline of subsequent generations. Termed Germ Cell Parasitism (GCP) this clonal dominance is heritable, stable, and reproducible, providing a tractable system in which to study cell competition.
Here we show a potential mechanism for GCP and cell competition in which GCP is partially due to differential homing of winners and losers to the germline niche and partially due to direct interaction between winner/loser cells and with the niche itself. We show that up-regulation of Delta and Jagged occurs in the winner GSCs, providing further support for the role of the Notch pathway in the process. Moreover, live-imaging of transplanted GSCs from winner/loser genotypes reveal that winner and loser GSCs both arrive in the developing germline niche, further suggesting a role for direct interaction between winner/loser GSCs within the niche. Based on these results, we propose that the basis of GSC competition resides in a combination of variation in homing ability and cell competition for niche occupancy controlled by differential expression of the Notch Pathway components.