Warts and Yorkie Mediate Intestinal Regeneration by Influencing Stem Cell Proliferation

Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Current biology: CB (Impact Factor: 9.57). 09/2010; 20(17):1580-7. DOI: 10.1016/j.cub.2010.07.041
Source: PubMed


Homeostasis in the Drosophila midgut is maintained by stem cells [1, 2]. The intestinal epithelium contains two types of differentiated cells that are lost and replenished: enteroendocrine (EE) cells and enterocytes (ECs). Intestinal stem cells (ISCs) are the only cells in the adult midgut that proliferate [3, 4], and ISC divisions give rise to an ISC and an enteroblast (EB), which differentiates into an EC or an EE cell [3-5]. If the midgut epithelium is damaged, then ISC proliferation increases [6-12]. Damaged ECs express secreted ligands (Unpaired proteins) that activate Jak-Stat signaling in ISCs and EBs to promote their proliferation and differentiation [7, 9, 13, 14]. We show that the Hippo pathway components Warts and Yorkie mediate a transition from low- to high-level ISC proliferation to facilitate regeneration. The Hippo pathway regulates growth in diverse organisms and has been linked to cancer [15, 16]. Yorkie is activated in ECs in response to tissue damage or activation of the damage-sensing Jnk pathway. Activation of Yorkie promotes expression of unpaired genes and triggers a nonautonomous increase in ISC proliferation. Our observations uncover a role for Hippo pathway components in regulating stem cell proliferation and intestinal regeneration.

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    • "); three components of the Hippo pathway (hpo, mats, and msn), which negatively regulates ISC proliferation (Li et al., 2014; Karpowicz et al., 2010; Ren et al., 2010; Staley and Irvine, 2010); and two components in the Scrib/Dlg tumor suppressor pathway (dlg and scrib), indicating that the Scrib/ Dlg pathway also negatively regulates ISC proliferation. "
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    ABSTRACT: The intestinal epithelium is the most rapidly self-renewing tissue in adult animals and maintained by intestinal stem cells (ISCs) in both Drosophila and mammals. To comprehensively identify genes and pathways that regulate ISC fates, we performed a genome-wide transgenic RNAi screen in adult Drosophila intestine and identified 405 genes that regulate ISC maintenance and lineage-specific differentiation. By integrating these genes into publicly available interaction databases, we further developed functional networks that regulate ISC self-renewal, ISC proliferation, ISC maintenance of diploid status, ISC survival, ISC-to-enterocyte (EC) lineage differentiation, and ISC-to-enteroendocrine (EE) lineage differentiation. By comparing regulators among ISCs, female germline stem cells, and neural stem cells, we found that factors related to basic stem cell cellular processes are commonly required in all stem cells, and stem-cell-specific, niche-related signals are required only in the unique stem cell type. Our findings provide valuable insights into stem cell maintenance and lineage-specific differentiation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 02/2015; 10(7). DOI:10.1016/j.celrep.2015.01.051 · 8.36 Impact Factor
    • "In vertebrates as in invertebrates, the nuclear translocation of Yki (named Yap in vertebrates) has been implicated in the stimulation of ISC proliferation upon gut injury (Karpowicz et al., 2010; Ren et al., 2010; Shaw et al., 2010; Staley and Irvine, 2010; Vanuytsel et al., 2013 "
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    ABSTRACT: The digestive tract is subjected to many aggressions throughout animal life. Since disruptions of gut physiology impact on animal fitness and survival, maintenance of gut integrity and functionality is essential for the individual. Over the last 40 years, research on rodents has aimed at understanding how cellular homeostasis of the digestive tract is maintained when challenged with disruptions. Following the discovery of stem cells in the digestive tract of Drosophila, a flurry of studies made an important contribution to our understanding of how the proliferation and the differentiation of these cells are controlled and participate in the renewal of the digestive tract. Insights into these mechanisms in Drosophila have revealed many similarities with mammalian intestinal stem cells. For instance, the highly conserved EGFR, JAK/STAT, Wingless/Wnt, Hedgehog, Integrins, BMP/TGFβ, Hippo and Insulin pathways all participate in adult intestinal cellular homeostasis. Here, we provide a literature review of recent advances in the field highlighting the adult Drosophila midgut as a convenient model for dissecting mechanisms involved in the maintenance of the cellular homeostasis of the digestive tract in conventionally reared conditions. In addition, we shed light on recently published data putting Drosophila forward as a genetic tool to decipher the mechanisms underlying intestinal diseases and intestinal tumour progression.
    Histology and histopathology 10/2014; 30(3). DOI:10.14670/HH-30.277 · 2.10 Impact Factor
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    • "JAK/STAT signaling is activated in Tao-deficient intestines We further examined the mechanism(s) by which Tao regulates midgut homeostasis. Previous studies have shown the essential roles of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway in regulating midgut homeostasis in response to environmental challenges (Amcheslavsky et al., 2009; Jiang et al., 2009, 2011; Karpowicz et al., 2010; Ren et al., 2010; Staley and Irvine, 2010). We first examined the activation of the JAK/STAT pathway in the Tao defective midguts using a 10 Â STAT-GFP reporter (Bach et al., 2007). "
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    ABSTRACT: The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. Here we show that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell (ISC) proliferation and midgut homeostasis loss. Meanwhile, we find that the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diap1 and bantam, is dramatically increased in Tao knockdown intestines. Consistently, we show that the Yorkie (Yki) acts downstream of Tao to regulate ISC proliferation. Together, our results provide insights into our understanding of the mechanisms of stem cell proliferation and tissue homeostasis control.
    Journal of Genetics and Genomics 08/2014; 41(8). DOI:10.1016/j.jgg.2014.05.007 · 3.59 Impact Factor
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