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 Sptzle (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.

Public Health Relevance

Optimal tissue fitness and animal health requires cells to cooperate with each other for normal tissue function. Unfit or uncooperative cells can arise by mutation in somatic tissues, potentially causing disease. Mechanisms to detect such mutant cells exist and elicit cell-cell interactions that prevent them from contributing to the animal. Although this process helps promote animal health, exploitation of the process could promote expansion of dangerous cells, as in cancer. Here we investigate the function of a secreted protein that mediates the recognition and elimination of unfit or dangerous cells. Understanding the process by which cells recognize aberrant cells could present therapeutic and preventative opportunities for diseases that exploit these detection mechanisms.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1)
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Melillo, Amanda A
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Columbia University (N.Y.)
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Alpar, Lale; Bergantiños, Cora; Johnston, Laura A (2018) Spatially Restricted Regulation of Spätzle/Toll Signaling during Cell Competition. Dev Cell 46:706-719.e5
Germani, Federico; Bergantinos, Cora; Johnston, Laura A (2018) Mosaic Analysis in Drosophila. Genetics 208:473-490
Johnston, Laura A (2014) Socializing with MYC: cell competition in development and as a model for premalignant cancer. Cold Spring Harb Perspect Med 4:a014274
Meyer, S N; Amoyel, M; Bergantiños, C et al. (2014) An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346:1258236
de la Cova, Claire; Senoo-Matsuda, Nanami; Ziosi, Marcello et al. (2014) Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. Cell Metab 19:470-83
Parisi, Federica; Riccardo, Sara; Zola, Sheri et al. (2013) dMyc expression in the fat body affects DILP2 release and increases the expression of the fat desaturase Desat1 resulting in organismal growth. Dev Biol 379:64-75
Rodrigues, Aloma B; Zoranovic, Tamara; Ayala-Camargo, Aidee et al. (2012) Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development 139:4051-61
de Beco, Simon; Ziosi, Marcello; Johnston, Laura A (2012) New frontiers in cell competition. Dev Dyn 241:831-41
Wells, Brent S; Johnston, Laura A (2012) Maintenance of imaginal disc plasticity and regenerative potential in Drosophila by p53. Dev Biol 361:263-76
Parisi, Federica; Riccardo, Sara; Daniel, Margaret et al. (2011) Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo. BMC Biol 9:65

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