Differential developmental blueprints of organ-intrinsic nervous systems.

The organ-intrinsic nervous system is a major interface between visceral organs and the brain, mediating important sensory and regulatory functions in the body-brain axis and serving as critical local processors for organ homeostasis. Molecularly, anatomically, and functionally, organ-intrinsic neurons are highly specialized for their host organs. However, the underlying mechanism that drives this specialization is largely unknown. Here, we describe the differential strategies utilized to achieve organ-specific organization between the enteric nervous system (ENS) 1 and the intrinsic cardiac nervous system (ICNS) 2 , a neuronal network essential for heart performance but poorly characterized. Integrating high-resolution whole-embryo imaging, single-cell genomics, spatial transcriptomics, proteomics, and bioinformatics, we uncover that unlike the ENS which is highly mobile and colonizes the entire gastrointestinal (GI) tract, the ICNS uses a rich set of extracellular matrix (ECM) genes that match with surrounding heart cells and an intermediate dedicated neuronal progenitor state to stabilize itself for a 'beads-on-the-necklace' organization on heart atria. While ICNS- and ENS-precursors are genetically similar, their differentiation paths are influenced by their host-organs, leading to distinct mature neuron types. Co-culturing ENS-precursors with heart cells shifts their identity towards the ICNS and induces the expression of heart-matching ECM genes. Our cross-organ study thus reveals fundamental principles for the maturation and specialization of organ-intrinsic neurons.