A Fasciclin 2 functional switch controls organ size in Drosophila

Abstract

How cell to cell interactions control local tissue growth to attain a species-specific pattern and organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2 (Drosophila NCAM), is expressed during the development of neural and epithelial organs. Genetic mosaic analysis of Fasciclin 2 reveals two complementary and opposing functions during imaginal disc growth, a cell autonomous requirement to promote growth and an opposite non-cell autonomous function to restrain growth at high expression levels. This non-cell autonomous function is mediated by the Fasciclin 2 heterophilic-binding partners CG15630 and CG33543. We show that EGFR physically interacts with Fasciclin 2 and mediates both the cell autonomous and the non-cell autonomous function. We further show that EGFR activity in turn promotes the cell autonomous expression of Fasciclin 2. We suggest that the auto-stimulatory loop between EGFR and Fasciclin 2 operates until reaching a threshold where the Fasciclin 2 non-cell autonomous function counteracts the growth-promoting activity of the homophilic interaction to terminate imaginal disc growth. Accordingly, we have found that Fasciclin 2 limits imaginal disc growth by the end of larval development. Cellular integration of Fasciclin 2 autonomous and non-cell autonomous signaling from neighbor cells may be a key regulator component to orchestrate the rate of intercalary cell proliferation and the final size of an organ.Author SummaryOne of the key unsolved problems in Biology is how a species-specific size is attained during animal development. During development cells should compute the amount of intercalary tissue growth to stop cell proliferation when reaching a correct pattern and size. Classic studies demonstrated that local cell interactions are key in controlling organ growth to reach a correct size and pattern in vertebrates and invertebrates. We present evidence strongly suggesting that Fasciclin 2 (the ortholog of NCAM in Drosophila) functions as a growth level switch to control pattern and organ size. First, we use genetic mosaic analyses to show that Fasciclin 2 promotes organ growth in a cell autonomous manner. Then we show that Fasciclin 2 restrains growth at high expression levels in a non-cell autonomous manner, and that there is a requirement for Fasciclin 2 to limit growth by the end of larval development. This function is dependent on Fasciclin 2 heterophilic binding partners CG15630 and CG33543. The Epidermal Growth Factor receptor mediates both functional facets of Fasciclin 2 and its activity in turn increases Fasciclin 2 cell autonomous expression, suggesting the existence of a functional auto-stimulatory loop. We also show that the Epidermal Growth Factor receptor and Fasciclin 2 physically interact. Our results show that the amount of Fasciclin 2 between cells determines organ size by acting as an expression level switch for EGFR function, and suggest that other specific CAM interactions may integrate similar expression level switches acting as a code for cells to compute local growth in attaining a species-specific organ size and shape.