Injury-stimulated Hedgehog signaling promotes regenerative proliferation of Drosophila intestinal stem cells.
Bottom Line: Inhibition of Hh signaling in the ISC lineage compromised injury-induced ISC proliferation but had little if any effect on homeostatic 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.
Affiliation: Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.Show MeSH
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Mentions: As an initial step to investigate whether Hh signaling plays a role in Drosophila adult midgut homeostasis, we generated GFP-labeled homozygous clones for ptc or smo mutations in 3- to 5-d-old adult females using the mosaic analysis with a repressible cell marker (MARCM) system (Lee and Luo, 2001). Two ptc alleles, ptcIIW (a allele) and ptcS2 (a strong allele), and smo3 (a allele) were used. After clone induction, adult flies were cultured at 18°C for certain periods of time before midguts were dissected for immunostaining. 10 d after clone induction (ACI), the majority of the control ISC lineage clones in the posterior region of midguts contained three to five cells whereas the majority of ptc mutant ISC lineage clones contained more than five cells (Fig. 1, A–C′ and E). Of note, we only included ISC lineage clones in the posterior region of midguts for quantification because of the regional difference in ISC proliferation rate (Buchon et al., 2013; Marianes and Spradling, 2013). The observed increase in clone size suggests that ptc mutant clones proliferated faster than the control clones, a notion that was confirmed by examining the mitotic index in midguts carrying ptc mutant clones or in which ptc was inactivated by RNAi (see results in Fig. 3).
Affiliation: Department of Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.