Abstract
Netrin receptors of the DCC/NEO/UNC-40/Frazzled family have well established roles in cell migration and axon guidance but can also regulate epithelial features such as adhesion, polarity and adherens junction (AJ) stability. Previously, we have shown that overexpression of Drosophila Frazzled (Fra) in the peripodial epithelium (PE) inhibits wing disc eversion and also generates cellular protrusions typical of motile cells. Here, we tested whether the molecular pathways by which Fra inhibits eversion are distinct from those driving motility. We show that in disc proper (DP) epithelial cells Fra, in addition to inducing F-Actin rich protrusions, can affect localization of AJ components and columnar cell shape. We then show that these phenotypes have different requirements for the three conserved Fra cytoplasmic P-motifs and for downstream genes. The formation of protrusions required the P3 motif of Fra, as well as integrins (mys and mew), the Rac pathway (Rac1, wave and, arpc3) and myosin regulatory light chain (Sqh). In contrast, apico-basal cell shape change, which was accompanied by increased myosin phosphorylation, was critically dependent upon the P1 motif and was promoted by RhoGef2 but inhibited by Rac1. Fra also caused a loss of AJ proteins (DE-Cad and Arm) from basolateral regions of epithelial cells. This phenotype required all 3 P-motifs, and was dependent upon the polarity factor par6. par6 was not required for protrusions or cell shape change, but was required to block eversion suggesting that control of AJ components may underlie the ability of Fra to promote epithelial stability. The results imply that multiple molecular pathways act downstream of Fra in epithelial cells.
Highlights
In recent years, it has become clear that cell surface receptors that mediate motility and guidance of migrating cells and axons can play a role in epithelial morphogenesis events [1]
The signaling pathways acting downstream of Deleted in Colorectal Carcinoma (DCC)-family receptors in growth cones and migrating cells are well studied, little is known about those operating in epithelial cells
We have presented evidence that the ability of Fra to generate motile protrusions, is molecularly separable from its ability to modulate epithelial cell shape and adherens junction (AJ) component localization, in that each of these responses has characteristic requirements for the Fra intracellular motifs, and for downstream genes
Summary
It has become clear that cell surface receptors that mediate motility and guidance of migrating cells and axons can play a role in epithelial morphogenesis events [1]. A case in point are the Netrin receptors of the Deleted in Colorectal Carcinoma (DCC) / Neogenin / UNC-40 / Frazzled family [2,3,4,5,6,7]. Netrins are a highly conserved family of secreted. Cell shape, and E-Cad localisation in epithelial cells analysis, decision to publish, or preparation of the manuscript
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