Key Developmental Protein Directs the Construction of Its Own Transport Pathways

Cytonemes are tendril-like appendages that developing cells use to communicate across large distances. Their cargo - including the key signaling protein Sonic Hedgehog (SHH) - is highly specific, but the mechanisms underlying this specificity were unclear. Now, scientists at St. Jude Children's Research Hospital have revealed how SHH activates a receptor protein cascade that travels with the protein into the cytoneme. This creates a bespoke highway connecting cells during embryonic development. The study, published today in Science Advances, showcases how cytonemes coordinate tissue development, with potential implications for developmental disorders and cancer.

"Cytonemes are built from actin and can grow to extraordinary lengths," said corresponding author Stacey Ogden, PhD, St. Jude Department of Cell & Molecular Biology. "We found evidence that Sonic Hedgehog may help direct the construction of their own long-range communication routes by recruiting receptors, which connect the signal to the actin machinery that drives cytoneme growth."

The researchers found that SHH was enlisting cytoneme "project managers" BOC and CDON, which bring in the "engineer" FARP1 and the "construction worker" Cdc42. When they removed BOC and CDON from SHH-producing cells, cytoneme numbers dropped, which affected how developing neural cells formed different cell types.

This signal cascade works together to make these extensions grow longer and longer - the more they signal, the longer the cytonemes become. That allows them to reach cells that are located very far away and deliver cargo that tells those cells what type of cell to become or how to behave, even across long distances."

Christina Daly, PhD, St. Jude Graduate School of Biomedical Sciences

Traditionally, BOC and CDON help cells receive SHH signals. This discovery implies a "reverse" role, where they also help transport the signal over long distances. "We determined that BOC and CDON can behave as co-receptors in receiving cells and also function in cytonemes as proteins that communicate with actin," Ogden said. "Their specific location within the cell and the proteins they interact with likely determine what function they are actively performing."

By understanding how SHH signaling is coordinated over long distances, researchers can begin to understand what happens when this vital signaling cascade goes awry. "Sonic Hedgehog is very important in tissue homeostasis; losing that communication during development can lead to developmental disorders, but losing it after development could cause fibrosis, interfering with wound healing or making an environment more conducive to tumor development," Ogden said. "The Sonic Hedgehog pathway does a lot at many different stages of life, which is why it's so important to know how it works."