Regulation of Stem Cell Activity and Behavior in the Drosophila Testis Niche by Heparan Sulfate

Abstract

Adult stem cells are multipotent cells that contribute to normal turnover and regeneration of mature tissues. They are regulated by components of their local microenvironment, called the stem cell niche. Despite the fact that many signaling pathways regulating different stem cell populations have been identified, the exact mechanisms by which these pathways influence stem cell behaviors in a context-dependent manner remain mostly a mystery. Additionally, recent evidence suggests that misregulation of the niche can predispose stem cells to cause cancer. The types of changes that can cause a healthy niche to become cancer-supporting have yet to be identified. Drosophila melanogaster has been useful in identifying new mechanisms of stem cell regulation that are conserved from invertebrates to mammals. Specifically, the Drosophila male germline stem cell (GSC) niche has been well-characterized and shows an extensive amount of conservation with the mammalian spermatogonial stem cell niche. These factors make it a useful model for identifying new mechanisms of stem cell control, or misregulation, that are likely conserved. Here we provide evidence that heparan sulfate (HS), a class of extracellular and highly-sulfated linear glycosaminoglycan chains, regulates the number and asymmetric division of GSCs in the Drosophila testis. We found that GSC number is sensitive to the levels of 6-O sulfate groups on HS. Loss of 6-O sulfation also disrupted Apc2 localization and GSC division orientation. These defects led to an increase in symmetric GSC divisions. We determined that HS in the niche was responsible for regulating these processes. We further demonstrated that the presence of HS on the niche is necessary to prevent tumor formation. Niche-specific HS loss led to formation of both somatic and germline tumors. This loss of hub HS resulted in ectopic Jak/Stat signaling outside the niche, and prevented normal somatic cell differentiation. These findings indicate that specific HS modifications provide a novel regulatory mechanism for control of stem cell asymmetric division and suggest that HS-mediated niche signaling acts upstream of GSC division orientation control. They also illustrate a role for HS in ensuring the integrity of the niche and preventing tumor formation.