Figure 8. Feedback mechanisms regulating cytoneme-mediated Bnl gradient formation.

(A) A hypothetical state of an isolated tracheal epithelial cell projecting cytonemes in random orientation prior to its establishment of cytoneme-mediated contact with a bnl source; Each recipient cell is endowed with a PntP1-dependent positive (green area) and Cut/Yan-dependent negative (red area) feedback, controlling the number of cytonemes and Btl (blue). (A’) Gradient formation is initiated when one or few tracheal cell(s) establish contact with a Bnl source. The ASP cells projecting Btl-containing cytonemes contact the bnl-source and directly receive Bnl signal (orange circles). Receptor-bound Bnl ligands move along the cytoneme surface and are endocytosed in the ASP cell to activate concentration-dependent gene activities: PntP1 at high-moderate levels, and Cut and Yan at gradually lower levels. PntP1 elicits positive feedback while Cut and Yan elicit negative feedback on production of Btl and cytonemes in tracheal cells, creating a steady-state graded pattern of Bnl-receiving cytonemes. Signaling through these cytonemes generates and reinforces the Bnl gradient. The positive (PntP1) and negative (Cut/Yan) feedback also inhibit each other, and thereby can shape the gradient following recipient tissue-specific morphology. (B) When few tracheal cells from a pre-existing branch establish contacts with a new proximal source, this mechanism can initiate a new local gradient and a new epithelial branch organization.