EGFR controls Drosophila tracheal tube elongation by intracellular trafficking regulation

Abstract

Development is governed by a few conserved signalling pathways. Amongst them, the EGFR pathway is used reiteratively for organ and tissue formation, and when dysregulated can lead to cancer and metastasis. Given its relevance, identifying its downstream molecular machinery and understanding how it instructs cellular changes is crucial. Here we approach this issue in the respiratory system of Drosophila. We identify a new role for EGFR restricting the elongation of the tracheal Dorsal Trunk. We find that EGFR regulates the apical determinant Crb and the extracellular matrix regulator Serp, two factors previously known to control tube length. EGFR regulates the organisation of endosomes in which Crb and Serp proteins are loaded. Our results are consistent with a role of EGFR in regulating Retromer/WASH recycling routes. Furthermore, we provide new insights into Crb trafficking and recycling during organ formation. Our work connects cell signalling, trafficking mechanisms and morphogenesis and suggests that the regulation of cargo trafficking can be a general outcome of EGFR activation.

Anisotropic Crb accumulation, modulated by Src42A, orients epithelial tube growth in Drosophila

“…Altogether our results are consistent with a model where the turnover of Crb protein is higher at LCJs. As we had previously described an endocyticrecycling turnover of Crb operating during tracheal development (20), the results suggest that Crb would be more prone to recycle and/or traffic to/at LCJs than to/at TCJs.…”

“…Quantification of the ratio of Crb accumulation in the SAR versus the AFR in control and EGFR CA expressing tracheal cells clearly indicated a significant decrease in the mutant condition ( Fig. 4C) (20). We now extended this analysis and quantified the apical surface area.…”

“…We further analysed this role by investigating the elongation of the tracheal cells during tube elongation. As above-mentioned, during tracheal development Crb becomes enriched in the SAR during the stages of DT elongation (20). This observation raises the possibility that Crb accumulation in the SAR drives, favours or facilitates apical membrane growth.…”

“…The results indicated that manipulation of EGFR activity has an effect on apical surface area. We showed that EGFR regulates the trafficking of different cargoes, in particular Crb and Serp (20), raising the possibility that the regulation of the apical surface area depends on targets different than Crb. However, the fact that Serp is not present in the SGs and that Crb has already been proposed to promote apical membrane growth (31,32), strongly suggest that Crb is at least one of the targets downstream of EGFR regulating apical growth.…”

“…These observations support the notion that tube elongation depends on the activity and coordination of different mechanisms (19), and indicate that Src is able to regulate several of them. (20,23,24). Roles for Src42A in protein trafficking have been proposed in different contexts (17,(25)(26)(27).…”