Mechanisms of cell competition that regulate growth during development

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 DESCRIPTION (provided by applicant): The central problem this work addresses is how cells communicate their fitness and recognize aberrant fitness differences that might endanger growing tissues. Much evidence indicates that the recognition of fitness disparities elicits interactions that prevent the weaker cells from contributing to the animal. This process is thought to promote optimal tissue and organismal fitness. Cell competition is a mechanism that facilitates this homeostatic process, and is initiated upon recognition of cells perceived as less it by their more robust neighbors. Examples of competitive behavior between cells of different fitness are numerous, but the best studied occur from expression differences in one of a number of ribosomal proteins (Rp), or the transcription factor Myc. The developing Drosophila wing has provided an essential, key paradigm for study of cell competition. Using this system we recently discovered that communication between the "winner" and "loser" cells is mediated by a novel signaling pathway consisting of components co-opted from innate immune pathways. Here we propose experiments to elucidate a specific aspect of this signaling mechanism, the role of Spätzle (Spz), a secreted cytokine that we identified as a key factor required for the elimination of loser cells in both Rp- and Myc-mediated cell competition. Spz, an NGF protein family member characterized by a critical cys-knot domain, functions as an activating ligand for the Toll pathway in D/V patterning of the Drosophila embryo and in larval and adult innate immunity. Our discovery that Spz is involved in transmitting information about cell fitness forms the basis of this application. Drosophila is unsurpassed for mosaic studies of cell-cell interactions in living animals and offers unparalleled genetic and molecular toolkits. The functional conservation of these signaling pathways suggests that unraveling their functions in cell competition could be transformative for an understanding of how exploitation to environmental barriers to growth leads to cancer or disease.