Defining the molecular mechanisms of cytoneme pathfinding

The National Institute of General Medical Sciences awarded St Jude Children's Research Hospital Inc. $153,560 on January 23, 2027, under the Biomedical Research and Research Training program (CFDA 93.859) to define the molecular mechanisms of cytoneme pathfinding and signal dispersal during tissue development.

The research will assess the functional contribution of cadherins to cytoneme navigation and signal deployment, and will build organoid models to interrogate cytoneme dynamics in complex cellular environments. The work addresses how cytoneme-resident adhesion proteins facilitate pathfinding and ligand cargo dispersal over long distances—mechanisms that remain poorly understood despite decades of research into morphogen signaling gradients and long-range intercellular communication during embryogenesis and organogenesis. The project will generate new model systems to assess cytoneme biology in three dimensions and inform understanding of the molecular structure of cytoneme contact points.

Performance occurs in Memphis, Tennessee, with a completion date of August 31, 2029. This is a Project Grant, the assistance type most common under NIGMS's portfolio approach to investigator-initiated biomedical research.

Abstract

Tissue development during embryogenesis relies on finely tuned signaling by morphogens, where both the timing of exposure and concentration of ligand dictate downstream intracellular signaling and cell fate specification. Many morphogens travel great distances from their sites of production to establish signaling gradients that guide differentiation of myriad cell types required for organogenesis. Despite decades of research, how signaling gradients are formed and reinforced to ensure appropriate long-range intercellular communication remains poorly defined. Cell contact-mediated signal transport by cytonemes is a morphogen dispersal model that can explain reliable transport of ligands to distant targets. IT has been shown that cytoneme-mediated signaling contributes to tissue patterning of multiple organs during vertebrate development however, the mechanisms by which cytonemes maintain structural integrity while navigating complex environments like an organizing tissue is not known. The mechanisms guiding their navigation and connections to deliver ligand cargo are also unanswered due to technical challenges associated with visualization of cytonemes in live tissue sections. This proposal will help close these knowledge gaps by testing the central hypothesis that cytoneme-resident adhesion proteins facilitate pathfinding and signaling ligand dispersal over long distances and will result in the generation of new model systems to assess cytoneme biology in 3D. Aim 1: assess the functional contribution of cadherins to cytoneme navigation and signal deployment. Aim 2: build organoid models to interrogate cytoneme dynamics in complex cellular environments. Completion of these aim will inform our understanding of the molecular structure of cytoneme contact points and provide new tools to investigate fundamental questions of cytoneme biology.