RESUMO
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.
Assuntos
Diferenciação Celular , Autorrenovação Celular , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Intestinos/fisiologia , Células-Tronco/citologia , Esteroides/farmacologia , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Drosophila , Proteínas de Drosophila/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Células-Tronco/metabolismo , Fatores de Transcrição/genéticaRESUMO
Mechanisms communicating changes in tissue stiffness and size are particularly relevant in the intestine because it is subject to constant mechanical stresses caused by peristalsis of its variable content. Using the Drosophila intestinal epithelium, we investigate the role of vinculin, one of the best characterised mechanoeffectors, which functions in both cadherin and integrin adhesion complexes. We discovered that vinculin regulates cell fate decisions, by preventing precocious activation and differentiation of intestinal progenitors into absorptive cells. It achieves this in concert with α-catenin at sites of cadherin adhesion, rather than as part of integrin function. Following asymmetric division of the stem cell into a stem cell and an enteroblast (EB), the two cells initially remain connected by adherens junctions, where vinculin is required, only on the EB side, to maintain the EB in a quiescent state and inhibit further divisions of the stem cell. By manipulating cell tension, we show that vinculin recruitment to adherens junction regulates EB activation and numbers. Consequently, removing vinculin results in an enlarged gut with improved resistance to starvation. Thus, mechanical regulation at the contact between stem cells and their progeny is used to control tissue cell number.
Mechanical changes in the environment have recently emerged as important signals of cell division and production of specialised cell types. Exactly how these forces are sensed and contribute to this process in living tissues, however, remains unclear. This question is particularly relevant in the lining of the gut. Endlessly exposed to intense mechanical stress and the passage of food, this tissue must constantly heal and renew itself. The intestinal cells that absorb nutrients from food, for example, are continually replaced as older cells are lost. This is made possible by immature 'progenitor' cells in the intestine dividing and maturing into various specialised cells including fully functional absorptive cells upon receiving the right mechanical and chemical signals. Errors in this carefully regulated process can result in too many or too few cells of the correct kind being produced, potentially leading to disease. To explore how mechanical forces may help to control the renewal and maturation of new intestinal cells, Bohère et al. examined the role of vinculin in the guts of fruit flies (where cell fate decisions involve mechanisms largely similar to humans). Vinculin can regulate cell fate, sense mechanical forces, and interact with the complex structures that physically connect cells to each other. Genetically altered flies that lacked vinculin had enlarged guts containing many more absorptive cells than those of normal flies, suggesting that the vinculin protein prevents over-production of these cells. Further experiments revealed that vinculin worked exclusively in the precursors of absorptive cells, keeping them in an immature state until new mature absorptive cells were required. This was achieved by vinculin acting upon and potentially strengthening the junctions connecting cells together. Finally, increasing the force within cells was shown to facilitate vinculin recruitment to these junctions. This study clarifies the role that mechanical forces at the interface between cells play in controlling when and how intestinal progenitors mature in an organism. If these findings are confirmed in mammals, Bohère et al. hope that they could inform how tissues cope with the changing mechanical landscape associated with ageing and inflammation.
Assuntos
Drosophila , Enterócitos , Animais , alfa Catenina/metabolismo , Vinculina/metabolismo , Drosophila/metabolismo , Enterócitos/metabolismo , Actinas/metabolismo , Caderinas/metabolismo , Integrinas , HomeostaseRESUMO
To compensate for accumulating damages and cell death, adult homeostasis (e.g., body fluids and secretion) requires organ regeneration, operated by long-lived stem cells. How stem cells can survive throughout the animal life remains poorly understood. Here we show that the transcription factor Shavenbaby (Svb, OvoL in vertebrates) is expressed in renal/nephric stem cells (RNSCs) of Drosophila and required for their maintenance during adulthood. As recently shown in embryos, Svb function in adult RNSCs further needs a post-translational processing mediated by the Polished rice (Pri) smORF peptides and impairing Svb function leads to RNSC apoptosis. We show that Svb interacts both genetically and physically with Yorkie (YAP/TAZ in vertebrates), a nuclear effector of the Hippo pathway, to activate the expression of the inhibitor of apoptosis DIAP1. These data therefore identify Svb as a nuclear effector in the Hippo pathway, critical for the survival of adult somatic stem cells.
Assuntos
Células-Tronco Adultas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Proteínas de Ligação a DNA/genética , Drosophila , Proteínas de Drosophila/genética , Marcação In Situ das Extremidades Cortadas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transativadores/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAPRESUMO
Animal development fundamentally relies on the precise control, in space and time, of genome expression. Whereas we have a wealth of information about spatial patterning, the mechanisms underlying temporal control remain poorly understood. Here we show that Pri peptides, encoded by small open reading frames, are direct mediators of the steroid hormone ecdysone for the timing of developmental programs in Drosophila. We identify a previously uncharacterized enzyme of ecdysone biosynthesis, GstE14, and find that ecdysone triggers pri expression to define the onset of epidermal trichome development, through post-translational control of the Shavenbaby transcription factor. We show that manipulating pri expression is sufficient to either put on hold or induce premature differentiation of trichomes. Furthermore, we find that ecdysone-dependent regulation of pri is not restricted to epidermis and occurs over various tissues and times. Together, these findings provide a molecular framework to explain how systemic hormonal control coordinates specific programs of differentiation with developmental timing.