Loss of<i>seven-up</i>from<i>Drosophila</i>R1/R6 photoreceptors reveals a stochastic fate choice that is normally biased by Notch

Miller, Adam C.; Seymour, Heather; King, Christopher; Herman, Tory

doi:10.1242/dev.016386

Cited by 38 publications

(43 citation statements)

References 55 publications

(83 reference statements)

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“…It has also been reported that the differentiation of these photoreceptors is purely stochastic and independent (11). Recent studies (12,13) have identified a mutual inhibitory gene regulation motif as the core system driving the stochastic differentiation, but the exact mechanism of the stochastic differentiation is still unknown. The similarities between this natural system and our engineered system, both in terms of observation and underlying GRN, suggest that stochastic and irreversible cellular developments in the fruit fly eye could be due to initialization of cells near basin boundaries of a multistable network.…”

Section: Discussionmentioning

confidence: 99%

“…Few mechanisms, however, have been proposed to explain the scenario of random and yet irreversible cell fate determination, which is commonly seen in development and cell differentiation. Recent studies (11)(12)(13) show examples of stochastic and irreversible cell differentiation in multicellular organisms, and they have identified that the central regulatory motif driving these stochastic differentiations is a mutual inhibitory gene regulatory network (GRN), a common topological module that can generate bistability. However, with neither fluctuating environmental cues nor spontaneous state transitioning identified in these cases, an understanding of how cells differentiate stochastically and irreversibly into distinct subpopulations remains elusive, especially when under the tight control of GRNs.…”

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confidence: 99%

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Engineering of regulated stochastic cell fate determination

Wu¹,

Li³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

157

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Both microbes and multicellular organisms actively regulate their cell fate determination to cope with changing environments or to ensure proper development. Here, we use synthetic biology approaches to engineer bistable gene networks to demonstrate that stochastic and permanent cell fate determination can be achieved through initializing gene regulatory networks (GRNs) at the boundary between dynamic attractors. We realize this experimentally by linking a synthetic GRN to a natural output of galactose metabolism regulation in yeast. Combining mathematical modeling and flow cytometry, we show that our engineered systems are bistable and that inherent gene expression stochasticity does not induce spontaneous state transitioning at steady state. Mathematical analysis predicts that stochastic cell fate determination in this case can only be realized when gene expression fluctuation occurs on or near attractor basin boundaries (the points of instability). Guided by numerical simulations, experiments are designed and performed with quantitatively diverse gene networks to test model predictions, which are verified by both flow cytometry and singlecell microscopy. By interfacing rationally designed synthetic GRNs with background gene regulation mechanisms, this work investigates intricate properties of networks that illuminate possible regulatory mechanisms for cell differentiation and development that can be initiated from points of instability.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Engineering of regulated stochastic cell fate determination

Wu¹,

Li³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

157

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“…These signals are necessary to activate pros and repress svp expression, respectively (Kauffmann et al, 1996;Miller et al, 2008;Xu et al, 2000). As the cone-cell precursor cells do not contact the determined R8 cell at the appropriate time, they will not 'see' the SEV ligand BOSS (Van Vactor et al, 1991).…”

Section: The Two-signal Model For R7-fate Determinationmentioning

confidence: 99%

Hindsight modulates Delta expression duringDrosophilacone cell induction

2009

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The induction of cone cells in the Drosophila larval eye disc by the determined R1/R6 photoreceptor precursor cells requires integration of the Delta-Notch and EGF receptor signaling pathways with the activity of the Lozenge transcription factor. Here, we demonstrate that the zinc-finger transcription factor Hindsight (HNT) is required for normal cone-cell induction. R-cells in which hindsight levels are knocked down using RNAi show normal subtype specification, but these cells have lower levels of the Notch ligand Delta. We show that HNT functions in the determined R1/R6 precursor cells to allow Delta transcription to reach high enough levels at the right time to induce the cone-cell determinants Prospero and D-Pax2 in neighboring cells. The Delta signal emanating from the R1/R6 precursor cells is also required to specify the R7 precursor cell by repressing seven-up. As hindsight mutants have normal R7 cell-fate determination, we infer that there is a lower threshold of Delta required for R7 specification than for cone-cell induction.

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“…When emc is absent, R7 precursors transform into R1/6 types, and so it appears to be a critical component of the N-induced R7 specification. 19 Another gene, seven-up (svp), encodes a steroid receptor-like protein that inhibits R7 development in R1/6/3/4 cells, 20 and is transcriptionally inactivated in R7 precursors by N, 21 while another gene, prospero (pros), encodes a homeodomain protein that prevents R7 precursors from adopting the R8 features, 22 and is transcriptionally regulated by N activity. 23 ommatidial development become photoreceptors.…”

Section: An Evolutionary Perspectivementioning

confidence: 99%

Stop and go

Mavromatakis

Tomlinson²

2012

Fly

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The Drosophila R7 photoreceptor precursor is directed to its fate by signals from adjacent cells that activate its Receptor Tyrosine Kinase (RTK) and Notch (N) signaling pathways. Counter-intuitively, the N activity both promotes and inhibits the photoreceptor fate in the R7 precursor. We offer an evolutionary perspective for this in which earlier ommatidia had fewer photoreceptors and used N to inhibit the addition of any more. When additional photoreceptors were added by evolution, an RTK signal was used to overcome the N inhibition in these cells, and these new additions potently activated N in their neighboring cells, preventing them from also responding to the RTK signal. The R7 precursor also receives this block, and requires robust RTK activation for it to become a photoreceptor. This is achieved by N transcriptionally activating a new RTK, one that is potently activated in the R7 precursor and sufficing to overcome the N inhibition. The unusually high RTK signal in R7 requires additional transduction components not needed when the signal is mild; in R7 the small GTPases Ras and Rap are both required to transduce the signal, but in other photoreceptors Ras alone suffices.

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Loss ofseven-upfromDrosophilaR1/R6 photoreceptors reveals a stochastic fate choice that is normally biased by Notch

Cited by 38 publications

References 55 publications

Engineering of regulated stochastic cell fate determination

Engineering of regulated stochastic cell fate determination

Hindsight modulates Delta expression duringDrosophilacone cell induction

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