Lineage and Organ Signals Sequentially Build Organ Intrinsic Nervous Systems [Spatial Transcriptomics]

Despite their importance, how these distinct neural architectures arise from a common neural crest cell (NCC) origin has remained unclear. Here, we present a systems-level, cross-organ analysis of OINS development, integrating lineage tracing, 3D imaging, single-cell transcriptomics, and genetic perturbations across heart, pancreas, intestine, and lungs.

We show that differences in NCC migratory trajectories prefigure the spatial architecture of OINSs, laying the foundation for organ-specific patterning. In contrast, molecular identity emerges largely in response to local environments, indicating that extrinsic cues play a major instructive role. Using in vitro co-cultures, we demonstrate that organ-derived cues reprogram intrinsic neurons toward organ-specific transcriptional profiles and direct neuronal differentiation, with extracellular matrix (ECM) contact identified as a central mediator.