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  • br Conclusions br Conflicts of

    2021-07-22


    Conclusions
    Conflicts of interest
    Research funding This work was financially supported by Shanghai Committee of Science and Technology (No. 16431903800).
    Main Text Developmental processes make usage of a surprisingly limited number of morphogens and signaling components to control a plethora of tissue specification and morphogenetic events. A prime example is the Ras/Erk MAPK cascade in which a complex atlas of spatially defined Erk signaling patterns has been documented over the last decades during development of flies and other organisms (Patel and Shvartsman, 2018). Classic genetic approaches have mapped the different molecular networks that control these co-existing Erk activity pools, but precise mechanistic insight into how a single pathway can control different developmental fates at different Drosophila mmae locations is still lacking. This is in part limited because long-term genetic perturbations lead to feedback inhibition, precluding the analysis of spatiotemporally regulated processes at adequate time/length scales. Recent progress in signaling optogenetics now solve some of these problems by allowing acute manipulation of cellular processes with unprecedented spatial and temporal resolution. In a previous paper, Toettcher and colleagues constructed and validated opto-SOS, an optogenetic actuator that allows precise spatiotemporal control of Erk signaling by blue light (Johnson et al., 2017). They found that such optogenetic control can induce higher levels of Erk activity than a panel of gain-of-function mutations, suggesting that this acute perturbation modality bypasses feedback inhibition due to long-term perturbation. Also, they found that only early embryogenesis (e.g., until 4 h post-fertilization) is sensitive to optogenetic Erk perturbations. After this interval, embryogenesis is robust against ectopic Erk activation. In the present study, Johnson and Toettcher (2019) more precisely dissect the logic of Erk-mediated spatiotemporal control of three distinct cell fates in the early embryo. At the anterior pole, Erk activation combined with Bicoid expression triggers head structures. On the lateral side, Erk controls neural ectoderm fates characterized by ind expression. At the posterior pole, Erk controls tissue contraction leading to gut endoderm fate characterized by mist expression. Intriguingly, a light-triggered, 30-min Erk pulse potentiates ind expression and the neural ectoderm fate, while a 120-min Erk pulse leads to loss of this fate. Posterior endoderm fate requires at least 1 h of light-triggered Erk signaling. This strongly suggests that these two different fates are controlled by distinct dynamic Erk signaling states of different durations. The authors take advantage of the power of optogenetics to explore additional aspects of Erk-mediated fate specification. First, they test how dynamic Erk signaling states are interpreted during fate specification. By optogenetic modulation of the width, the frequency, and the amplitude of Erk signaling, they infer that embryonic fates are determined by the cumulative load rather than the persistence of the dynamic Erk signaling state. Second, they observe that different Erk-dependent transcriptional outputs react differently to temporal Erk inputs. Some transcriptional outputs vary linearly, while others react non-linearly, and display switch-like behavior with increasing Erk input. Together, these results strengthen the concept that dynamic Erk signaling states specify fate decisions, a concept that has been widely documented in cultured cells (Albeck et al., 2013, Santos et al., 2007). Further, the precision level of optogenetic perturbations provides new hints about the spatiotemporal scale at which transcriptional outputs fluctuate, providing fresh insights about the potential transcriptional network architecture that decode dynamic Erk signaling states. The arena is open to systematically interrogate the dynamics of transcriptional outputs in response to dynamic optogenetic inputs at higher spatiotemporal resolution to characterize in detail how different transcriptional networks that operate in space and time specify different fates during embryogenesis.