Feedback regulation of cytoneme-mediated transport shapes a tissue-specific FGF morphogen gradient

Feedback regulation of cytoneme-mediated transport shapes a tissue-specific FGF morphogen gradient

Gradients of signaling proteins are essential for inducing tissue morphogenesis. However, mechanisms of gradient formation remain controversial.

Acting as a morphogen in the ASP, FGF activates concentration-dependent gene expression, inducing pointed-P1 at higher and cut at lower levels. The transcription-factors Pointed-P1 and Cut antagonize each other and differentially regulate formation of FGFR-containing cytonemes, creating regions with higher-to-lower numbers of FGF-receiving cytonemes. These results reveal a robust mechanism where morphogens self-generate precise tissue-specific gradient contours through feedback regulation of cytoneme-mediated dispersion.

When an embryo develops, its cells must work together and ‘talk’ with each other so they can build the tissues and organs of the body. A cell can communicate with its neighbors by producing a signal, also known as a morphogen, which will tell the receiving cells what to do. Once outside the cell, a morphogen spreads through the surrounding tissue and forms a gradient: there is more of the molecule closer to the signaling cells and less further away. The cells that receive the message respond differently depending on how much morphogen they get, and therefore on where they are placed in the embryo.

How morphogens move in tissues to create gradients is still poorly understood.

Despite advances in our understanding of signal transduction pathways, how signals disperse and how the dispersion mechanism is dynamically modulated to shape gradients in three-dimensional tissue structures are poorly understood. Moreover, the formation of signal gradients is unexplored in most morphogenetic contexts, so we do not know how dispersion of the signals through extracellular space can generate the required diversity in gradient shapes and contours for a multitude of tissue architectures.

At this point, we do not know why and how Bnl is released from producing cells only at cytoneme-source membrane contact sites. Understanding the mechanisms underlying this process is an important new direction for future investigations.

Future live imaging analyses are required to elucidate the mechanisms of cytoneme pathfinding.

How morphogen gradients are produced in tissues is a long-standing central question.

how are the cytoneme patterns developed and maintained in the tissue? Answering this question was expected to provide the basis by which cytonemes create and regulate gradient shapes and tissue patterns.

The consequence is a regulatory loop that controls the generation and reinforcement of different numbers of cytonemes and levels of Bnl signaling, making the contours of the Bnl gradient robust, precisely tissue-specific, and self-sustaining.

Given the commonality of fundamental signaling events mediated by conserved signaling proteins, feedback regulation of cytoneme-mediated transport may offer an explanation for why signal gradients are so precise, yet adaptable and for how diverse tissue morphologies can result from just one signal transduction pathway.