EGFR and JAK/STAT, which act upstream of Notch to trigger proliferation and promote enterocyte survival in the midgut (Jiang

INTRODUCTION To compensate for cell loss, most animal tissues maintain slowly proliferating populations of stem cells that are able to differentiate on demand. Given the great potential of stem cells for the management of many human diseases, it is important to understand in detail the molecular pathways that control the biology of stem cells, including their origin, pattern of proliferation and migration during development. In this paper, we focus on the development of intestinal stem cells (ISCs) that form part of the gut and excretory system of the fruit fly Drosophila melanogaster. Stem cells have been described for the Drosophila endodermal midgut, as well as for the ectodermal Malpighian tubules and hindgut. In the midgut and Malpighian tubules, stem cells are scattered more or less evenly over the outer (basal) surface of the epithelium (Ohlstein and Spradling, 2006; Micchelli and Perrimon, 2006; Singh et al., 2007). In the hindgut, proliferating cells are confined to a narrow segment that forms the hindgut-midgut boundary (hindgut proliferation zone, HPZ) (Takashima et al., 2008). A similar ring of proliferating cells also exists in the adult foregut (Singh et al., 2011). Stem cells develop as part of the adult gut progenitors that can be already distinguished in the embryonic and larval gut (Jiang and Edgar, 2009; Mathur et al., 2010; Takashima et al., 2011a; Takashima et al., 2011b). Small clusters (‘nests’) of dividing adult midgut progenitors (AMPs) are distributed over the larval midgut. Two ring-shaped domains of proliferating cells flanking the midgut anteriorly and posteriorly, form the primordia of the adult foregut and hindgut, respectively. During pupal development, most of the larval gut undergoes programmed cell death, similar to what has been described for some vertebrate systems undergoing metamorphosis (Ishizuya-Oka and Shi, 2007; Hasebe et al., 2011). The adult gut primordia spread, fuse together and differentiate as the adult foregut, midgut and hindgut. Only the larval Malpighian tubules, according to previous reports, survive metamorphosis and become the adult tubules. Recent genetic studies have elucidated several of the signaling pathways that control the proliferation and differentiation of gut progenitors in the larva, and ISCs in the adult. Among these are: the Notch and Wnt/Wingless pathways, which keep gut progenitors and ISCs in a dividing non-differentiated state (Ohlstein and Spradling, 2006; Ohlstein and Spradling, 2007; Micchelli and Perrimon, 2006; Lin et al., 2008; Lee et al., 2009; Xu et al., 2011); EGFR and JAK/STAT, which act upstream of Notch to trigger proliferation and promote enterocyte survival in the midgut (Jiang et al., 2009; Jiang et al., 2011; Liu et al., 2010; Xu et al., 2011); and Hedgehog, which promotes enterocyte differentiation in the hindgut (Takashima et al., 2008). However, many of the mechanisms that specify ISCs, in particular the signaling events that, during metamorphosis, select these cells from among the adult gut progenitors and keep them undifferentiated, are still unknown. It is also not clear how the ISCs, once determined, migrate to their final position. Notably, the site of origin of ISCs populating the adult Malpighian tubules has remained unknown so far. In this paper, we have investigated the origin of stem cells that form near the boundary between midgut, hindgut and Malpighian tubules. Our findings show that, during early stages of metamorphosis, two unsuspected, major movements of gut progenitors take place. First, adult midgut progenitors (AMPs) give rise not only to the adult midgut epithelium, but also move posteriorly to form the adult ureters. During later pupal stages, subsets of AMPs migrate from the ureters onto the Malpighian Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.