In the Drosophila ovary, developing follicles are composed of somatic follicle cells surrounding germline cysts that will become the egg. The follicle cells derive from somatic stem cells, which give rise to follicle cell precursors, which i turn differentiate into mature follicle cells. It has been reported that the Wnt (Wg) and Hedgehog (Hh) signaling pathways stimulate somatic stem cell proliferation in the Drosophila ovary, as the hyper-activation of these pathways results in excess follicle cells. These signals are produced by cells that are 3-5 cell diameters away from the stem cells, raising the question of how the signals are transported to the responding stem cells. In our continuing studies of the extracellular matrix-degrading MMP family of proteases, we have observed that when Mmp2 function is lost conditionally in adult females, the follicle stem cells over-proliferate in the ovry. This phenotype is consistent with Mmp2 inhibiting the Wg and/or Hh signaling pathway. This R03 proposal describes a small study to determine how Mmp2 regulates somatic stem cell proliferation.
In Aim1, we will determine if Wg, Hh, or both pathways are altered, through analysis of genetic interactions and gene expression patterns.
In Aim 2, we will determine how Mmp2 mediates long-range signaling over several cell diameters, by asking if Mmp2-GFP is itself transported, and testing candidate transport models including lipid particle transport, HSPG transport, and GPI-anchor mediated transport. We are well situated to perform these studies, as the PI has been investigating Drosophila MMPs for a decade and originally trained in the Drosophila ovary, and the postdoc performing the experiments has experience with stem cell proliferation in the Drosophila ovary. Additionally, our lab is located immediately adjacent t labs that study wnt and hh signaling in vertebrates. Our studies have high significance, as all three of these pathways - MMP, Wg, and Hh - have been implicated in tumor progression, and Wnt signaling is central to stem cell regulation in epithelia such as skin and intestine. Our findings propose a new model that MMPs limit these growth-promoting signals to stem cells. We expect the small study proposed here will lay the foundation for a larger mechanistic analysis of how MMPs regulate stem cell proliferation, in both development and cancer.
Controlling stem cell proliferation is important in diverse settings from normal organ formation to regenerative medicine, and dysregulation of cell proliferation is the central event underlying cancer. We are analyzing the role of genes known to be important in cancer, the Wnt and Hedgehog signaling pathway and the matrix metalloproteinases, and we hypothesize that they interact in previously unsuspected ways to regulate stem cell proliferation during follicle formation in the ovary. Our findings will be relevnt to a variety of developmental biology questions as well as to cancer biology.
|Wang, Xiaoxi; Page-McCaw, Andrea (2014) A matrix metalloproteinase mediates long-distance attenuation of stem cell proliferation. J Cell Biol 206:923-36|