Fasciclin 2 engages EGFR in an auto-stimulatory loop to promote imaginal disc cell proliferation in Drosophila

How cell to cell interactions control local tissue growth to attain a species-specific organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2, is expressed during the development of neural and epithelial organs. Fasciclin 2 is a homophilic-interaction protein that shows moderate levels of expression in the proliferating epithelia and high levels in the differentiating non-proliferative cells of imaginal discs. Genetic interactions and mosaic analyses reveal a cell autonomous requirement of Fasciclin 2 to promote cell proliferation in imaginal discs. This function is mediated by the EGFR, and indirectly involves the JNK and Hippo signaling pathways. We further show that Fasciclin 2 physically interacts with EGFR and that, in turn, EGFR activity promotes the cell autonomous expression of Fasciclin 2 during imaginal disc growth. We propose that this auto-stimulatory loop between EGFR and Fasciclin 2 is at the core of a cell to cell interaction mechanism that controls the amount of intercalary growth in imaginal discs. Author summaryA key problem in developmental biology is how species-specific organ size is determined. Control of organ growth occurs at different levels of organization, from the systemic to the cell to cell interaction level. During nervous system development cell contact interactions regulate axon growth. Here, we show that one of the cell adhesion molecules involved in controlling axon growth, the Drosophila NCAM ortholog Fasciclin 2, also controls epithelial organ growth and size. Fasciclin 2 is expressed in highly dynamic but moderate levels during cell proliferation in imaginal discs (precursor epithelial organs of the adult epidermis), and at much higher level in pre-differentiating and differentiating cells in imaginal discs. During imaginal disc growth cell interactions mediated by Fasciclin 2 promote Epidermal Growth Factor Receptor function and cell proliferation. In turn, Epidermal Growth Factor Receptor activity promotes Fasciclin 2 expression, creating a cell autonomous auto-stimulatory loop that maintains cell proliferation. This function of Fasciclin 2 is reciprocal to its reported function in pre-differentiating and differentiating cells in imaginal discs, where it acts as an Epidermal Growth Factor Receptor repressor. Our study suggests that the amount of Fasciclin 2 may determine a threshold to grow or stop growing during epithelial organ development.

Automated summary

The study reveals the crucial role of the Drosophila Neural Cell Adhesion Molecule Fasciclin 2 in regulating epithelial organ growth and size by promoting cell proliferation through interaction with EGFR, creating a self-stimulatory loop. This mechanism controls intercalary growth in imaginal discs and may determine the threshold for epithelial organ development.