The temporal context of cytoneme-mediated contacts governs the interpretation of inductive cues during lineage specification
July 17
This study interrogated the temporal dynamics that sculpt how epithelial collectives interpret cytoneme contact as an inductive signal. Colony replicates (n = 137) were exposed to a microfluidic arena in which individual edge cells had to resolve whether neighboring cells were probing or soliciting one of three morphogens. Each edge cell extended a cytoneme three times per trial, with the presence, frequency and order of direct membrane contacts varied across six stimulation regimes. Robust differences emerged across all contact regimes. Colonies were most likely, and responded most rapidly, with lineage-specific transcription when a single brief membrane apposition was embedded between two retractive sweeps toward the same morphogen source. These data indicate that the relative temporal context of contact and withdrawal, rather than contact frequency or immediacy, governs the inductive power of cytoneme signaling. Parallel results obtained with aggregates composed of human pluripotent stem cells or bio-engineered synthetic epithelia demonstrate that temporal parsing of membrane cues is a general property of developing tissues. Together, these findings push cytoneme biology beyond static contact paradigms and provide design rules for engineering dynamic membrane behaviors in programmable tissues to elicit naturalistic and intuitive morphogenetic responses.