Lineage and organ signals sequentially build organ intrinsic nervous systems

Organ intrinsic nervous systems (OINSs) are critical components of the body–brain axis and coordinate visceral organ function with systemic physiological control1–7. Despite their importance, how these distinct neural architectures arise from a common neural crest cell 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 the heart, pancreas, intestine and lungs. We show that differences in neural crest cell migratory trajectories prefigure the spatial architecture of OINSs, laying the foundation for organ-specific patterning. By contrast, molecular identity emerges largely in response to local environments, indicating that extrinsic cues have a major instructive role. Using in vitro co-cultures, we demonstrate that organ-derived cues reprogramme intrinsic neurons towards organ-specific transcriptional profiles and direct neuronal differentiation, with extracellular matrix (ECM) contact as a central mediator. In vivo, ECM–integrin signalling supports neurogenesis of intrinsic cardiac neurons, and ECM crosslinking stabilizes their stereotyped ganglionic organization. Together, these findings reveal that OINS diversity arises through a dual logic: lineage programmes prefigure spatial frameworks, whereas organ-specific cues instruct final molecular identities and architectural precision. This work establishes a conceptual paradigm for how organs actively build their nervous systems, illuminating principles that underlie body–brain integration. Systems-level analyses of organ intrinsic nervous systems reveal that these networks are initially configured by lineage-dependent programmes, and their architecture and molecular identity are refined by intra-organ specific local cues.