Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult <i>Drosophila</i> posterior midgut

Zeng, Xiankun; Hou, Steven X.

doi:10.1242/dev.113357

Cited by 181 publications

(188 citation statements)

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“…It has recently been proposed that EE cells could differentiate directly from ISCs rather than indirectly from EE-committed EBs (Biteau and Jasper, 2014;Zeng and Hou, 2015). Because Ttk69 depletion does not compromise ISC self-renewal, this indicates that the extra EE cells are differentiated from EBs rather than ISCs.…”

Section: Discussionmentioning

confidence: 98%

Ttk69 acts as a master repressor of enteroendocrine cell specification inDrosophilaintestinal stem cell lineages

et al. 2015

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In adult Drosophila midgut, intestinal stem cells (ISCs) periodically produce progenitor cells that undergo a binary fate choice determined primarily by the levels of Notch activity that they receive, before terminally differentiating into enterocytes (ECs) or enteroendocrine (EE) cells. Here we identified Ttk69, a BTB domain-containing transcriptional repressor, as a master repressor of EE cell specification in the ISC lineages. Depletion of ttk69 in progenitor cells induced ISC proliferation and caused all committed progenitor cells to adopt EE fate, leading to the production of supernumerary EE cells in the intestinal epithelium. Conversely, forced expression of Ttk69 in progenitor cells was sufficient to prevent EE cell specification. The expression of Ttk69 was not regulated by Notch signaling, and forced activation of Notch, which is sufficient to induce EC specification of normal progenitor cells, failed to prevent EE cell specification of Ttk69-depleted progenitors. Loss of Ttk69 led to derepression of the acheate-scute complex (AS-C) genes scute and asense, which then induced prospero expression to promote EE cell specification. These studies suggest that Ttk69 functions in parallel with Notch signaling and acts as a master repressor of EE cell specification in Drosophila ISC lineages primarily by suppressing AS-C genes.

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Section: Discussionmentioning

confidence: 98%

Ttk69 acts as a master repressor of enteroendocrine cell specification inDrosophilaintestinal stem cell lineages

et al. 2015

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“…In the Drosophila midgut, the ISCs give rise to two types of daughter progenitors, the undifferentiated enteroblast (EB) and the preenteroendocrine ( pre-EE) cell (Beehler-Evans and Micchelli, 2015;Biteau and Jasper, 2014;Micchelli and Perrimon, 2006;Ohlstein and Spradling, 2006;Zeng and Hou, 2015;Zielke et al, 2014). EBs and pre-EEs differentiate into absorptive enterocytes (ECs) and secretory enteroendocrine (EE) cells, respectively.…”

Section: Tnks Is Essential For Control Of Isc Proliferation In the Admentioning

confidence: 99%

The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila

et al. 2016

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Wnt/β-catenin signaling controls intestinal stem cell (ISC) proliferation, and is aberrantly activated in colorectal cancer. Inhibitors of the ADP-ribose polymerase Tankyrase (Tnks) have become lead therapeutic candidates for Wnt-driven cancers, following the recent discovery that Tnks targets Axin, a negative regulator of Wnt signaling, for proteolysis. Initial reports indicated that Tnks is important for Wnt pathway activation in cultured human cell lines. However, the requirement for Tnks in physiological settings has been less clear, as subsequent studies in mice, fish and flies suggested that Tnks was either entirely dispensable for Wntdependent processes in vivo, or alternatively, had tissue-specific roles. Here, using null alleles, we demonstrate that the regulation of Axin by the highly conserved Drosophila Tnks homolog is essential for the control of ISC proliferation. Furthermore, in the adult intestine, where activity of the Wingless pathway is graded and peaks at each compartmental boundary, Tnks is dispensable for signaling in regions where pathway activity is high, but essential where pathway activity is relatively low. Finally, as observed previously for Wingless pathway components, Tnks activity in absorptive enterocytes controls the proliferation of neighboring ISCs non-autonomously by regulating JAK/STAT signaling. These findings reveal the requirement for Tnks in the control of ISC proliferation and suggest an essential role in the amplification of Wnt signaling, with relevance for development, homeostasis and cancer.

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“…1B). Progenitors specialise in producing either nutrient-absorbing enterocytes or secretory enteroendocrine cells (Guo and Ohlstein, 2015;Micchelli and Perrimon, 2006;Ohlstein and Spradling, 2006;Zeng and Hou, 2015). The precursors of enterocytes, called enteroblasts (EBs), are frequently found forming pairs with ISCs (Ohlstein and Spradling, 2006;Micchelli and Perrimon, 2006;Bardin et al, 2010;de Navascués et al, 2012) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Diversity of fate outcomes in cell pairs under lateral inhibition

et al. 2017

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Cell fate determination by lateral inhibition via Notch/Delta signalling has been extensively studied. Most formalised models consider Notch/Delta interactions in fields of cells, with parameters that typically lead to symmetry breaking of signalling states between neighbouring cells, commonly resulting in salt-and-pepper fate patterns. Here, we consider the case of signalling between isolated cell pairs, and find that the bifurcation properties of a standard mathematical model of lateral inhibition can lead to stable symmetric signalling states. We apply this model to the adult intestinal stem cell (ISC) of Drosophila, the fate of which is stochastic but dependent on the Notch/Delta pathway. We observe a correlation between signalling state in cell pairs and their contact area. We interpret this behaviour in terms of the properties of our model in the presence of population variability in contact areas, which affects the effective signalling threshold of individual cells. Our results suggest that the dynamics of Notch/Delta signalling can contribute to explain stochasticity in stem cell fate decisions, and that the standard model for lateral inhibition can account for a wider range of developmental outcomes than previously considered.

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Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut

Cited by 181 publications

References 50 publications

Ttk69 acts as a master repressor of enteroendocrine cell specification inDrosophilaintestinal stem cell lineages

Ttk69 acts as a master repressor of enteroendocrine cell specification inDrosophilaintestinal stem cell lineages

The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila

Diversity of fate outcomes in cell pairs under lateral inhibition

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