Steroid‐dependent switch of OvoL/Shavenbaby controls self‐renewal versus differentiation of intestinal stem cells

Abstract

Adult stem cells must continuously fine‐tune their behavior to regenerate damaged organs and avoid tumors. While several signaling pathways are well known to regulate somatic stem cells, the underlying mechanisms remain largely unexplored. Here, we demonstrate a cell‐intrinsic role for the OvoL family transcription factor, Shavenbaby (Svb), in balancing self‐renewal and differentiation of Drosophila intestinal stem cells. We find that svb is a downstream target of Wnt and EGFR pathways, mediating their activity for stem cell survival and proliferation. This requires post‐translational processing of Svb into a transcriptional activator, whose upregulation induces tumor‐like stem cell hyperproliferation. In contrast, the unprocessed form of Svb acts as a repressor that imposes differentiation into enterocytes, and suppresses tumors induced by altered signaling. We show that the switch between Svb repressor and activator is triggered in response to systemic steroid hormone, which is produced by ovaries. Therefore, the Svb axis allows intrinsic integration of local signaling cues and inter‐organ communication to adjust stem cell proliferation versus differentiation, suggesting a broad role of OvoL/Svb in adult and cancer stem cells.

Pri smORF Peptides Are Wide Mediators of Ecdysone Signaling, Contributing to Shape Spatiotemporal Responses

“…Consistently, we found that pri epidermal expression during both embryogenesis and metamorphosis is activated in response to ecdysone (Chanut-Delalande et al, 2014). Recent studies further show that pri expression is also controlled by ecdysone in the embryonic tracheal cells (Taira et al, 2021), as well as in the adult stem cells that regenerate the gut (Al Hayek et al, 2021) and kidneys (Bohère et al, 2018) to ensure homeostasis of vital functions across adulthood.…”

“…Recent studies have revealed that ecdysone signaling is essential to adapt the behavior of intestinal stem cells in adult females, as part of a post-mating response (Ahmed et al, 2020;Zipper et al, 2020). We found that Pri peptides are playing an important role in this ovary-to-gut interorgan communication, being able to substitute for ecdysone signaling in intestinal stem cells (Al Hayek et al, 2021). Hence, Pri peptides appear as key mediators of ecdysone, in a broad variety of tissues throughout development, as well as in adult stem cells.…”

“…Individual pri enhancers can also be active in different tissues and/or developmental stages; this feature is called pleiotropy (Preger-Ben Noon et al, 2018). PriA represents a striking case of a pleiotropic enhancer that is expressed in both the embryonic epidermis and the leg primordium, as well as in renal (Bohère et al, 2018) and intestinal (Al Hayek et al, 2021) adult stem cells. Of note, other genes of the ecdysone cascade possess pleiotropic enhancers, as seen with EcR, Eip75B, and ftz-f1 that are driven by enhancers active in both somatic and germline tissues during oogenesis (McDonald et al, 2019).…”

An amuse-bouche of stem cell regulation: Underlying principles and mechanisms from adult Drosophila intestinal stem cells

“…Both SP and Ecdysone directly promote ISC proliferation and gut expansion [81,82]. Mechanistically, Ecdysone induces the expression of EGFR pathway genes (spi, krn, rho) via Eip75B [83] and promotes the Pri mediated post-translational modification of the mitogenic factor Shavenbaby [84]. Ecdysone also stimulates food intake through myosuppressin (Ms) expressing neurons mediated crop enlargement [85].…”

Partial EMT in Squamous Cell Carcinoma: A Snapshot

“…In addition, systemic steroid hormones produced by the ovaries regulate the conversion between Svb inhibitors and activators. Therefore, the Svb axis allows the internal integration of local signal cues and interorgan communication to regulate the proliferation and differentiation of stem cells and has a wide range of roles in adult stem cells and cancer stem cells 128 . A recent study showed that the interaction of EMT-TFs (Snail, Zeb1/2) and the epithelial stabilizing factor Svb can regulate stemness and pEMT 129 .…”