UIF, a large transmembrane protein with EGF-like repeats, can antagonize Notch signaling in Drosophila. Hongtao Zhang^1,2, Gengqiang Xie^1,4, Jun Ma^1,3, Renjie Jiao¹. 1) State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, the Chinese Academy of Sciences, Beijing, China; 2) Graduate School of the Chinese Academy of Sciences, Beijing, China; 3) Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Childrens Research Foundation, Cincinnati, OH, USA; 4) Department of Biological Science, The Florida State University,Tallahassee, FL 32306, USA.

   Notch signaling is a highly conserved pathway in multi-cellular organisms ranging from flies to humans. The diversity, specificity and sensitivity of the Notch signaling output are regulated at distinct levels, particularly at the level of ligand-receptor interactions. Here, we show that the Drosophila gene uninflatable (uif), which encodes a large transmembrane protein with eighteen EGF-like repeats in its extracellular domain, can antagonize the canonical Notch signaling pathway. Overexpression of Uif causes Notch signaling defects, which can be rescued by Notch target gene expression. Further experiments suggest that overexpression of Uif inhibits Notch signaling in cis and acts at a step that is dependent on the extracellular domain of Notch, which suggest that Uif can alter the accessibility of the Notch extracellular domain to its ligands during Notch activation. However, uif loss-of-function did not reveal any detectable phenotypes that are reminiscent of Notch activation. Nevertheless, a wing cell size reduction upon Uif depletion indicates that Uif may have a role in the control of cell growth. We further demonstrate that the intracellular domain of Uif is responsible, to a large extent, for its role in cell size control. Further investigations combining genetic and biochemical approaches are in progress to shed light on how Uif controls cell growth.