Fasciclin 2 functions as an expression-level switch on EGFR to control organ shape and size inDrosophila

Fasciclin 2 ( Drosophila NCAM) is a homophilic Cell Adhesion Molecule expressed at moderate levels in the proliferating epithelial cells of imaginal discs, where it engages EGFR in a cell autonomous auto-stimulatory loop that promotes growth along larval development. In addition, Fasciclin 2 is expressed at high levels in the pre-differentiating cells of imaginal discs. Gain-of-function genetic analysis shows that Fasciclin 2 acts as a non-cell autonomous repressor of EGFR when high expression levels are induced during imaginal disc growth. Loss-of-function genetic analysis shows that this Fasciclin 2 functional facet is required at the end of larval development and it is mediated by interaction with IgCAMs CG15630 (Fipi) and CG33543 (Elff). Thus, Fasciclin 2 bears two complementary functional roles which correspond with different levels of expression. The combined results from loss- and gain-of-function analyses suggest a scenario where the Fasciclin 2/EGFR cell autonomous auto-stimulatory loop promotes cell proliferation until reaching a Fasciclin 2 expression threshold where its non-cell autonomous function stops growth. Thus, 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 and shape of an organ. Author Summary How organ size and shape are controlled during development is a central and still unsolved problem in developmental biology. Growth control must be precise and local to account for the vast variation of organ shapes and sizes during evolution. Here I show that the expression of Fasciclin 2 ( Drosophila NCAM) controls whether to grow or not to grow by controlling EGFR activity in epithelial organs. Fasciclin 2 homophilic binding promotes cell autonomous activity of EGFR at low and medium levels of expression, which in turn causes a cell autonomous increase of Fasciclin 2 expression. In addition, at high expression levels, Fasciclin 2 function switches to a non-cell autonomous repressor of EGFR by interacting with its heterophilic partner IgCAMs Fipi and Elff. Thus, the two functional facets of Fasciclin 2, as cell autonomous activator and non-cell autonomous repressor of EGFR, constitute an expression-level switch for growth in the control of organ shape and size.