Netrin-dependent downregulation of Frazzled/DCC is required for the dissociation of the peripodial epithelium in Drosophila.
Netrins are secreted chemoattractants with roles in axon guidance, cell migration and epithelial plasticity. Netrin-1 also promotes the survival of metastasized cells by inhibiting the pro-apoptotic effects of its receptor Deleted in Colorectal Carcinoma (DCC). Here we report that Netrins can also regulate epithelial dissociation during Drosophila wing eversion. During eversion, peripodial epithelial cells lose apico-basal polarity and adherens junctions, and become migratory and invasive--a process similar to an epithelial-mesenchymal transition. Loss of netrinA inhibits the breakdown of cell-cell junctions, leading to eversion failure. In contrast, the Netrin receptor Frazzled blocks eversion when overexpressed, whereas frazzled RNAi accelerates eversion in vitro. In peripodial cells Frazzled is endocytosed, and undergoes NetA-dependent degradation, which is required for eversion. Finally, we provide evidence that Frazzled acts through the ERM-family protein Moesin to inhibit eversion. This mechanism may also help explain the role of Netrin and DCC in cancer metastasis.
Department of Genetics, University of Melbourne, Melbourne, Victoria 3010, Australia.
Rosemary
R
Manhire-Heath
Sofia
S
Golenkina
Robert
R
Saint
Michael J
MJ
Murray
D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D015536:Down-Regulation; D004330:Drosophila / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins; D004848:Epithelium / Q000502:physiology; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism; D008675:Metamorphosis, Biological; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D000075385:Netrins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014921:Wings, Animal / Q000254:growth & development*
D029721:Drosophila Proteins; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C000617352:NetA protein, Drosophila; D000075386:Netrin Receptors; D000075385:Netrins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617310:fra protein, Drosophila; C099886:moesin, Drosophila; D000075388:Netrin-1; D046988:Proteasome Endopeptidase Complex