Mechanism of Cell Competition

Recently, genetic analyses in Drosophila have revealed various genes that regulate the competitive behavior of cells. Among these, the neoplastic tumor-suppressor genes (nTSGs) have been shown to fulfill two significant functions requisite for organ size control: first, establishing apicobasal cell polarity as a principle of epithelial tissue organization and appropriate timing of terminal differentiation and, second, exerting cell-proliferation control as a primary factor in tissue growth. Our recent studies revealed that nTSG Lgl and its novel binding partner Mahjong (Mahj) are involved in cell competition. In the mosaic Drosophila wing imaginal discs, mahj-/- or lgl-/- cells adjacent to wild-type cells undergo apoptosis, whereas mahj-/- or lgl-/- cells that are not adjacent to wild-type cells do not. The nonautonomous apoptosis in these mutant cells is suppressed by inhibition of the JNK pathway. Furthermore, overexpression of Mahj in lgl-/- mutant cells suppresses JNK activation and blocks apoptosis of lgl-/- mutant cells in the wild-type wing-disc epithelium. In collaboration with Dr. Fujita at University College London, we found that Mahj-knockdown mammalian MDCK cells were also eliminated by wildtype cells through cell competition. Taken together, our data suggest that Mahjong and Lgl belong to a molecular pathway that plays an evolutionarily conserved role in regulating cellular competitiveness.

In summary, the three major areas of research in my lab are independent yet connected—proper differentiation of follicle cells is key to the establishment of oocyte polarity, and cell competition involves intercellular communication and regulation of cell proliferation. Through the study of temporal and spatial regulation of important genes and pathways in our model systems, we will develop a more comprehensive picture of the molecular mechanisms orchestrating egg development and gain a deeper understanding of how basic cellular functions such as proliferation, differentiation, and growth are regulated in development.

Figure 1. Loss of Mahj function induces cell competition in Drosophila wing disc epithelium. (A) Wing and leg discs of homozygous mahj1 mutant third-instar Drosophila larvae stained with anti-Ci155 (red) and anti-Engrailed (green) antibodies. (B–F) Wing discs with mahj−/− (lacking GFP), wild-type (expressing GFP strongly), and mahj+/− clones (expressing GFP moderately) at 72 h (B), 96 h (C, E, and F), and 120 h (D) after clone induction. (E) A Z-stack projection of confocal images of a wing disc. Basally extruded apoptotic cells were excluded from the analysis. (F) Magnified images of (E). (E and F) Apoptotic cells were labeled with anti-cleaved Caspase-3 antibody (red). Nuclei were stained with DAPI (blue). (G) Quantification of apoptotic cells in the mahj1 mosaic wing discs showing non-cell-autonomous apoptosis in mahj−/− cells. The results represent means±SD (n = 34 discs, *p<0.001). (Tamori et al., 2010)