Shavenbaby protein isoforms orchestrate the self-renewalversusdifferentiation ofDrosophilaintestinal stem cells

Abstract

Signaling pathways are key regulators of adult stem cell homeostasis and underlying mechanisms are often deregulated in cancers. Recent studies of epithelial tumors have involved OvoL/Svb transcription factors, which produce isoforms with antagonistic activities. Here we show that Svb, the unique OvoL factor in Drosophila, directly integrates multiple signaling inputs to coordinate the behavior of adult intestinal stem cell lineage. Under steady state, Svb mediates Wnt and EGFR signaling to ensure stem cell renewal and progenitor survival. This requires the post-translational processing of Svb into a transcriptional activator by Polished rice (Pri) regulatory peptides, under the regulation of ecdysone signaling. In response to PDM1, Svb expression is specifically maintained in enterocytes where it acts as a transcriptional repressor sufficient to override mitogenic signals and impose differentiation. Altogether, these results demonstrate that the OvoL/Svb transcriptional switch controls the balance between stem cell survival, selfrenewal and differentiation.

Multiple Roles of the Polycistronic Gene Tarsal-less/Mille-Pattes/Polished-Rice During Embryogenesis of the Kissing Bug Rhodnius prolixus

“…Cas9/CRISPR editing technology has been established in other non-model arthropod species (Gilles et al, 2015) and its establishment in R. prolixus might help to unveil the specific function of each small peptide present in Rp-mlpt transcript at different developmental stages. Recent studies demonstrated that mlpt is required for Svb activation in adult tissues, particularly in nephric and intestinal D. melanogaster stem cells (Al Hayek et al, 2019). Since mlpt is also expressed in R. prolixus digestive tract (Ribeiro et al, 2014 and our own observations), it will also be interesting to address the functional role of this gene containing smORFs in other developmental contexts.…”

Alternate Grainy head isoforms regulateDrosophilamidgut intestinal stem cell differentiation

“…Two other studies of transcription factor function in the Drosophila midgut have reported isoform-specific regulation of differentiation (Al Hayek et al, 2019, Tang et al, 2018. The POU/Oct transcription factor Nubbin/Pdm1 is expressed in enterocytes (Lee et al, 2009) and has been reported to repress escargot expression during EC differentiation (Korzelius et al, 2014).…”

“…In this case there may not be direct antagonism between Svb isoforms as Pri is expressed in ISCs/EBs where it results in production of Svb ACT which functions to promote ISC proliferation, whereas Svb REP is expressed in ECs and promotes differentiation. Although, Svb REP forces differentiation even when expressed in a genetic background that favours stem cell proliferation (Al Hayek et al, 2019).…”

A complex gene regulatory architecture underlies the development and evolution of cuticle morphology in Drosophila

“…In addition, OVOL1 and OVOL2 are required in vertebrates for epithelial maintenance by suppressing the epithelial-mesenchymal transition [49][50][51][52]. Interestingly, it has been shown that Svb interacts with epithelialmesenchymal transition promoting factors during stem cell homeostasis in Drosophila [43,44]. Thus, it is likely that a Svb-like protein had a role in germline development and epithelial differentiation/tissue homeostasis in the urbilaterian ancestor (Figure 2), although studies in more organisms are required to confirm this hypothesis.…”

“…Indeed, svb and tal have a role in the formation of leg joints in Drosophila and other insects [38,42], as well as a function in insect segmentation, which was lost in flies [38]. Moreover, it has been shown that the homeostasis and differentiation of renal and intestinal stem cells in Drosophila are also regulated by svb and tal [43,44]. It is likely that Svb interacts with distinct partners in the many contexts in which it is active, with the concomitant activation of different sets of target genes.…”