Summary Food texture has enormous affects on food preferences. However, the mechanosensory cells and key molecules responsible for sensing the physical properties of food are unknown. Here, we show that akin to mammals, the fruit fly, Drosophila melanogaster, prefers food with a specific hardness or viscosity. This food texture discrimination depends upon a previously unknown multidendritic (md-L) neuron, which extends elaborate dendritic arbors innervating the bases of taste hairs. The md-L neurons exhibit directional selectivity in response to mechanical stimuli. Moreover, these neurons orchestrate different feeding behaviors depending on the magnitude of the stimulus. We demonstrate that the single Drosophila transmembrane channel-like (TMC) is expressed in md-L neurons, where it is required for sensing two key textural features of food—hardness and viscosity. We propose that md-L neurons are long-sought-after mechanoreceptor cells through which food mechanics are perceived and encoded by a taste organ, and this sensation depends on TMC.

A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained–but not pulsatile–ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.

12Epithelial tissues are constantly challenged by individual cell fate decisions while 13 maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their 14 signaling states and cellular behaviors creating competitive interactions that are poorly 15 understood. Here we show that the temporal patterns of MAPK activity are decoded by the 16 ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote 17 extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to 18 maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the 19 stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that 20 the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace 21 unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity 22 coordinates both single and collective cell behaviors to maintain tissue homeostasis. 23 24 27 cancers 1 . In normal conditions the ERK pathway promotes proliferation, differentiation, survival 28 and cell migration 2 . Conversely, during oncogenesis mutations or amplification of ERK pathway 29 components can also promote oncogene-induced senescence 3 (OIS) or cellular extrusion from 30 epithelial monolayers 4,5 . The mechanisms underlying dose dependent effects of ERK signaling 31 have been intensely studied using bulk cell population assays. However, the advent of single cell 32 analysis has shown that single cells often behave qualitatively different than bulk populations. In 33 fact, in vivo and in vitro studies have now shown that pulsatile or sustained ERK activity have 34 different effects on cell fate 6-12 . Whether oncogenic perturbations also have different functional 35 outcomes depending on downstream signaling dynamics remains unknown. To address this 36 question, an isogenic single-cell approach with temporal control of oncogene expression is 37 needed. 38 39 Recent in vivo studies revealed that oncogene expression can trigger cell-cell competition and 40 tissue level responses involving normal neighboring cells 13-16 . During these events, the 41 mechanistic basis of competition and the signaling events involved in recognition between normal 42 and diseased cells are poorly understood. Coincidentally, propagating ERK signaling waves that 43 depend on the sheddase ADAM17 have been observed in mouse epidermis and intestinal 44 organoids, but the physiological role of these collective signaling events in homeostasis remains 45 unclear 7,8,17 . Understanding of the context-dependent mechanisms of paracrine signaling and cell-46 cell competition upon oncogene expression holds the key to unlocking new therapeutic strategies. 47 48 Here we combine live cell imaging of signaling biosensors with inducible expression of oncogenes 49 to study the cell autonomous and non-cell autonomous effects of oncogene expression in 50 epithelial monolayers. Our data shows that pulsa...

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