Dpp/Gbb signaling is required for normal intestinal regeneration during infection

Abstract

Maintaining tissue homeostasis is a critical process during infection and inflammation. Tissues with a high intrinsic turnover, such as the intestinal epithelium, must launch a rapid response to infections while simultaneously coordinating cell proliferation and differentiation decisions. In this study, we searched for genes required for regeneration of the Drosophila intestine, and thereby affecting overall organism survival after infection with pathogenic bacteria. We found that Dpp/Gbb (BMP) signaling is essential for normal midgut regeneration, and that infection induces the BMP signaling ligands Dpp and Gbb. We demonstrate that Dpp is induced in visceral muscle and required for signaling activation. Subsequently, Gbb is induced in enterocytes after oral infection. Loss-of Dpp signaling in ISCs and transient committed progenitors called enteroblasts (EBs), or in EBs alone, led to a blockage in EC differentiation or maturation. Furthermore, our data show that down-regulation of Dpp signaling in the precursor cells including EBs also resulted in an increased number of abnormally small Pdm1-positive cells, suggesting a role of Dpp/Gbb signaling in EC growth. In addition, we show that Dpp/Gbb signaling acted downstream or in parallel to the Notch pathway to promote EC differentiation and growth. Our results suggest that Dpp/BMP signaling plays an important role in EBs to maintain tissue integrity and homeostasis during pathogenic infections.

Dpp regulates autophagy-dependent midgut removal and signals to block ecdysone production

“…During embryonic gut formation Dpp is required in a complex feedback, both within and between tissue layers, to maintain the correct patterning of homeotic gene expression during midgut morphogenesis [46,47]. In the Drosophila adult gut, Dpp has multiple complex roles in the regulation of ISCs in both an autocrine and paracrine mode [48][49][50][51][52][53]. Additionally, the TGF-β/ activin pathway acts as a carbohydrate-sensing mechanism in the adult midgut to regulate digestive enzyme expression [54].…”

Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration

“…Previous studies have reported that BMP signaling is activated in ISCs, enteroblasts and enterocytes, and that it plays several roles, including regulation of ISC division and differentiation, enterocyte survival and copper cell differentiation (Ayyaz et al, 2015;Guo et al, 2013;Li et al, 2013a,b;Tian and Jiang, 2014;Zhou et al, 2015). Our RT-qPCR analysis did not detect any difference in the mRNA levels of dpp and glass bottom boat (gbb), which encode ligands of the BMP pathway, between the wild-type and Sulf1 mutant midgut samples (Fig.…”

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

“…Conversely, hyperactivation of either pathway leads to ISC hyperproliferation (Lin et al, 2008) (Lee et al, 2009) (Jiang et al, 2011) (Buchon et al, 2010) (Cordero et al, 2012b) (Cordero et al, 2012a). Multiple sources of the BMP ligands Dpp and Gbb, maintain intestinal homeostasis by constraining ISC proliferation (Tian and Jiang, 2014) (Li et al, 2013b) (Zhou et al, 2014). Recently, Hedgehog (Hh) signalling has emerged as a positive regulator of basal ISC proliferation in the midgut.…”

“…Finally, activation of DPP/BMP signalling is required for the return to homeostasis after repair of the damage epithelium has been achieved (Zhou et al, 2014) (Guo et al, 2013).…”