Injury-stimulated Hedgehog signaling promotes regenerative proliferation of Drosophila intestinal stem cells.
Many adult tissues are maintained by resident stem cells that elevate their proliferation in response to injury. The regulatory mechanisms underlying regenerative proliferation are still poorly understood. Here we show that injury induces Hedgehog (Hh) signaling in enteroblasts (EBs) to promote intestinal stem cell (ISC) proliferation in Drosophila melanogaster adult midgut. Elevated Hh signaling by patched (ptc) mutations drove ISC proliferation noncell autonomously. Inhibition of Hh signaling in the ISC lineage compromised injury-induced ISC proliferation but had little if any effect on homeostatic proliferation. Hh signaling acted in EBs to regulate the production of Upd2, which activated the JAK-STAT pathway to promote ISC proliferation. Furthermore, we show that Hh signaling is stimulated by DSS through the JNK pathway and that inhibition of Hh signaling in EBs prevented DSS-stimulated ISC proliferation. Hence, our study uncovers a JNK-Hh-JAK-STAT signaling axis in the regulation of regenerative stem cell proliferation.
Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.
Aiguo
A
Tian
Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.
Qing
Q
Shi
Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.
Alice
A
Jiang
Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.
Shuangxi
S
Li
Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.
Bing
B
Wang
Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 jin.jiang@utsouthwestern.edu.
Jin
J
Jiang
D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing
D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D011956:Receptors, Cell Surface; C070844:ptc protein, Drosophila; C077245:hh protein, Drosophila