Making cells inter-connected for signaling communication: a developmental view of cytonemes

Cellular communication is a cornerstone of metazoan development, orchestrating cell behavior, differentiation, and tissue formation. Morphogens, key signaling molecules for patterning tissue architecture, are traditionally thought to act through diffusion or endocytosis but struggle to explain precise long-range gradient formation in complex tissues. The discovery of cytonemes, specialized actin-based membrane extensions, has introduced a novel mechanism for direct intercellular signaling. Their dynamic structure allows for long-range signaling, ensuring specificity and accuracy in morphogen delivery, which is essential for proper tissue patterning and cell differentiation. In this review, we summarize the latest advances of cytoneme research across different model organisms by focusing on the regulatory mechanisms and functional roles in stem cells and developmental disorders. We establish cytonemes as fundamental mediators of intercellular communication and emphasize their pivotal roles in developmental biology and potential implications in regenerative medicine and cancer therapy.