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bioRxiv · 10.1101/2023.12.12.571306

Differential developmental blueprints of organ-intrinsic nervous systems

Hsu, I.-U.·Lin, Y.·Guo, Y.·Xu, Q. J.·Shao, Y.·Wang, R. L.·Yin, D.·Zhao, J.·Young, L. H.·Zhao, H.·Zhang, L.·Chang, R. B.
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Abstract

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.

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Hsu, I.-U., Lin, Y., Guo, Y., Xu, Q. J., Shao, Y., Wang, R. L., Yin, D., Zhao, J., Young, L. H., Zhao, H., Zhang, L., Chang, R. B.. 2023-12-13. Differential developmental blueprints of organ-intrinsic nervous systems. https://doi.org/10.1101/2023.12.12.571306

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