Abstract
ABSTRACTTissue homeostasis is maintained by differentiated progeny of residential stem cells. Both extrinsic signals and intrinsic factors play critical roles in the proliferation and differentiation of adult intestinal stem cells (ISCs). However, how extrinsic signals are transduced into ISCs still remains unclear. Here, we find that heparan sulfate (HS), a class of glycosaminoglycan (GAG) chains, negatively regulates progenitor proliferation and differentiation to maintain midgut homeostasis under physiological conditions. Interestingly, HS depletion in progenitors results in inactivation of Decapentaplegic (Dpp) signaling. Dpp signal inactivation in progenitors resembles HS-deficient intestines. Ectopic Dpp signaling completely rescued the defects caused by HS depletion. Taken together, these data demonstrate that HS is required for Dpp signaling to maintain midgut homeostasis. Our results provide insight into the regulatory mechanisms of how extrinsic signals are transduced into stem cells to regulate their proliferation and differentiation.
Highlights
Adult stem cells are responsible for tissue homeostasis in the tissues in which they reside; frequently lost cells are constantly replenished by the progeny of stem cells
Loss of heparan sulfate (HS) in progenitors leads to disruption of midgut homeostasis In order to identify intrinsic factors regulating the proliferation and differentiation of intestinal stem cells (ISCs), we carried out a genome-wide RNAi screen using the esgGal4, UAS-GFP, tubGal80ts driver in the posterior midgut. esgGal4 is expressed in progenitors (ISCs and EBs) in the midgut. 11,316 RNAi lines from Vienna Drosophila RNAi Center (VDRC), Fly stocks of National Institute of Genetics (NIG-FLY), and the Transgenic RNAi Project (TRiP) at Harvard Medical School/Tsinghua University were screened
The number of esg+ cells was significantly increased when sfl was depleted in progenitors. esg+ cells formed clusters and GFP was expressed in polyploid cells, indicative of midgut homeostasis loss (Fig. 1B,C,I). sfl encodes the only Drosophila HS N-deacetylase/ N-sulfotransferase, which catalyzes the first step of HS modification (Esko and Lindahl, 2001; Lin, 2004)
Summary
Adult stem cells are responsible for tissue homeostasis in the tissues in which they reside; frequently lost cells are constantly replenished by the progeny of stem cells. The proliferation and differentiation of adult stem cells must be tightly balanced. Disruption of this balance will lead to either excessive stem cells or stem cell depletion, eventually resulting in various diseases, such as cancer (Lin, 2008; Morrison and Spradling, 2008; Radtke and Clevers, 2005; Xie and Spradling, 1998). Understanding of the underlying mechanisms controlling adult stem cell proliferation and differentiation will provide insight into the potential development of therapeutic applications for human diseases. The posterior midgut of the adult Drosophila intestine is an excellent system to study how stem cell proliferation and differentiation are regulated. Adult intestinal stem cells (ISCs) are interspersed along the base membrane of the Drosophila adult
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