“…This provides strong support for the timer model over the threshold model for a second direct Ftz target, suggesting that this might be a more general way in which Ftz activates its targets. The observation is also consistent with earlier work showing that the timing of engrailed activation did not change as the copy number of Ftz was altered 14 . Interestingly, engrailed is activated about 10 minutes after the autoregulatory enhancer ( Fig 7c ), indicating that the precise value of the activation time could be enhancer specific.…”
Section: Resultssupporting
confidence: 92%
“…Over the course of an hour the initially broad Ftz pattern matures into a series of seven asymmetric stripes 11,12 . The anterior edges of these stripes specify the even-numbered compartment boundaries of the embryo [13][14][15] (Fig 1a-i). These boundaries play a crucial role in development as signaling centers that are maintained throughout the life of the fly 16 .…”
Section: (Fig 1b and Fig S1)mentioning
confidence: 99%
“…The anterior edges of the Ftz stripes are sharply defined, with a single row of nuclei containing high levels of Ftz positioned right next to a row of low-Ftz nuclei 17 . This binary protein pattern is essential for setting up the compartment boundary, by defining where two different selector genes, engrailed and wingless , are expressed 14,15,18,19 . How the two ftz enhancers work together to define the Ftz expression pattern is still unclear, but individually they have been extensively characterized.…”
Coordinating the action of different enhancers is crucial to correctly specify cell fate decisions during development. Yet it remains poorly understood how the activity of multiple enhancers is choregraphed in time. To shed light on this question we used new live imaging approaches to quantify transcription and protein expression in single cells of Drosophila melanogaster embryos. We employed these tools to dissect the regulation of Fushi tarazu (Ftz), a transcription factor expressed in a series of stripes by two distinct enhancers: autoregulatory and zebra. The anterior edges of the Ftz stripes are sharply defined and specify essential signaling centers. Here, we determined the time at which each boundary cell commits to either a high-Ftz or low-Ftz fate using dynamic features of time-resolved Ftz protein traces. By following the activity of each enhancer individually, we showed that the autoregulatory enhancer does not establish this fate choice. Instead, it perpetuates the decision defined by zebra. This is contrary to the prevailing view that autoregulation drives the fate decision by causing bi-stable Ftz expression. Furthermore, we showed that the autoregulatory enhancer is not activated based on a Ftz concentration threshold, but through a timing-based mechanism. We hypothesize that this is regulated by a set of pioneer-like transcription factors, which have recently been shown to act as timers in the embryo. Our work provides new insight into the genetic mechanisms that directly regulate the dynamics of gene regulatory networks, and supports the emerging view that this regulation is vital for reliable cell fate specification.
“…This provides strong support for the timer model over the threshold model for a second direct Ftz target, suggesting that this might be a more general way in which Ftz activates its targets. The observation is also consistent with earlier work showing that the timing of engrailed activation did not change as the copy number of Ftz was altered 14 . Interestingly, engrailed is activated about 10 minutes after the autoregulatory enhancer ( Fig 7c ), indicating that the precise value of the activation time could be enhancer specific.…”
Section: Resultssupporting
confidence: 92%
“…Over the course of an hour the initially broad Ftz pattern matures into a series of seven asymmetric stripes 11,12 . The anterior edges of these stripes specify the even-numbered compartment boundaries of the embryo [13][14][15] (Fig 1a-i). These boundaries play a crucial role in development as signaling centers that are maintained throughout the life of the fly 16 .…”
Section: (Fig 1b and Fig S1)mentioning
confidence: 99%
“…The anterior edges of the Ftz stripes are sharply defined, with a single row of nuclei containing high levels of Ftz positioned right next to a row of low-Ftz nuclei 17 . This binary protein pattern is essential for setting up the compartment boundary, by defining where two different selector genes, engrailed and wingless , are expressed 14,15,18,19 . How the two ftz enhancers work together to define the Ftz expression pattern is still unclear, but individually they have been extensively characterized.…”
Coordinating the action of different enhancers is crucial to correctly specify cell fate decisions during development. Yet it remains poorly understood how the activity of multiple enhancers is choregraphed in time. To shed light on this question we used new live imaging approaches to quantify transcription and protein expression in single cells of Drosophila melanogaster embryos. We employed these tools to dissect the regulation of Fushi tarazu (Ftz), a transcription factor expressed in a series of stripes by two distinct enhancers: autoregulatory and zebra. The anterior edges of the Ftz stripes are sharply defined and specify essential signaling centers. Here, we determined the time at which each boundary cell commits to either a high-Ftz or low-Ftz fate using dynamic features of time-resolved Ftz protein traces. By following the activity of each enhancer individually, we showed that the autoregulatory enhancer does not establish this fate choice. Instead, it perpetuates the decision defined by zebra. This is contrary to the prevailing view that autoregulation drives the fate decision by causing bi-stable Ftz expression. Furthermore, we showed that the autoregulatory enhancer is not activated based on a Ftz concentration threshold, but through a timing-based mechanism. We hypothesize that this is regulated by a set of pioneer-like transcription factors, which have recently been shown to act as timers in the embryo. Our work provides new insight into the genetic mechanisms that directly regulate the dynamics of gene regulatory networks, and supports the emerging view that this regulation is vital for reliable cell fate specification.
“…However, this cell death appears to be an indirect effect (Hughes and Krause, 2001). Similarly, pair-rule genes regulate segment border formation indirectly, via activation of the segment polarity genes such as en and wg (Carroll, 1990; Carroll et al, 1988; DiNardo and O'Farrell, 1987; Howard and Ingham, 1986; Ingham et al, 1988; Jaynes and Fujioka, 2004; Lawrence and Johnston, 1989; Lawrence et al, 1987; Lawrence and Pick, 1998). In addition to this, segment-polarity-independent roles for the pair-rule genes in morphogenesis have been revealed by careful studies from the Wieschaus lab (reviewed in (Dawes-Hoang and Wieschaus, 2001; Wieschaus et al, 1991).…”
During development, cascades of regulatory genes act in a hierarchical fashion to subdivide the embryo into increasingly specified body regions. This has been best characterized in Drosophila, where genes encoding regulatory transcription factors form a network to direct the development of the basic segmented body plan. The pair-rule genes are pivotal in this process as they are responsible for the first subdivision of the embryo into repeated metameric units. The Drosophila pair-rule gene fushi tarazu (ftz) is a derived Hox gene expressed in and required for the development of alternate parasegments. Previous studies suggested that Ftz achieves its distinct regulatory specificity as a segmentation protein by interacting with a ubiquitously expressed cofactor, the nuclear receptor Ftz-F1. However, the downstream target genes regulated by Ftz and other pair-rule genes to direct segment formation are not known. In this study, we selected candidate Ftz targets by virtue of their early expression in Ftz-like stripes. This identified two new Ftz target genes, drumstick (drm) and no ocelli (noc), and confirmed that Ftz regulates a serotonin receptor (5-HT2). These are the earliest Ftz targets identified to date and all are coordinately regulated by Ftz-F1. Engrailed (En), the best-characterized Ftz/Ftz-F1 downstream target, is not an intermediate in regulation. The drm genomic region harbors two separate 7-stripe enhancers, identified by virtue of predicted Ftz-F1 binding sites and these sites are necessary for stripe expression in vivo. We propose that pair-rule genes, exemplified by Ftz/Ftz-F1, promote segmentation by acting at different hierarchical levels, regulating first, other segmentation genes; second, other regulatory genes that in turn control specific cellular processes such as tissue differentiation; and, third, 'segmentation realizator genes' that are directly involved in morphogenesis.
“… 9 This binary protein pattern specifies a compartment boundary that forms an essential foundation of the body plan. 6 , 10 , 11 We refer to the high-Ftz row of cells as the posterior boundary (PB) nuclei because they are posterior of the future compartment boundary and, similarly, the row of neighboring low-Ftz nuclei are referred to as the anterior boundary (AB) nuclei ( Figure 1 Ai). Figure 1 Visualizing Ftz protein dynamics in real time using the LlamaTag (A) Ftz expression in the fly embryo.…”
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