Abstract The enteric nervous system (ENS) is the intrinsic nervous system of the gut and controls essential functions, such as gut motility, intestinal barrier function, and water balance. The ENS displays a complex 3D architecture within the context of the gut and specific transcriptional states needed to control gut homeostasis. During development, the ENS develops from enteric neural progenitor cells (ENPs) that migrate into the gut and differentiate into functionally diverse neuron types. Incorrect ENS development can disrupt ENS function and induce various gut disorders, including the congenital disease Hirschsprung disease, or various other functional gut neurological disorders, such as esophageal achalasia. In this study, we used the zebrafish larval model and performed whole gut spatial genomic analysis (SGA) of the differentiating ENS at cellular resolution. To that end, a pipeline was developed that integrated early and late developmental ENS stages by linking various spatial and transcriptional dimensions to discover regionalized cellular groups and their co-expression similarity. We identified 3D networks of intact ENS surrounding the gut and predicted cellular connectivity properties based on the stage. Spatial variable genes, such ashoxb5b,hoxa4a,etv1, andret, were regionalized along gut axes, suggesting they may have a precise spatiotemporal control of ENS development. The application of SGA to ENS development provides new insights into its cellular transcriptional networks and interactions, and provides a baseline data set to further advance our understanding of gut neurodevelopmental disorders such as Hirschsprung disease and congenital enteric neuropathies. 
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                            How to Heal the Gut’s Brain: Regeneration of the Enteric Nervous System
                        
                    
    
            The neural-crest-derived enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal (GI) tract and controls all gut functions, including motility. Lack of ENS neurons causes various ENS disorders such as Hirschsprung Disease. One treatment option for ENS disorders includes the activation of resident stem cells to regenerate ENS neurons. Regeneration in the ENS has mainly been studied in mammalian species using surgical or chemically induced injury methods. These mammalian studies showed a variety of regenerative responses with generally limited regeneration of ENS neurons but (partial) regrowth and functional recovery of nerve fibers. Several aspects might contribute to the variety in regenerative responses, including observation time after injury, species, and gut region targeted. Zebrafish have recently emerged as a promising model system to study ENS regeneration as larvae possess the ability to generate new neurons after ablation. As the next steps in ENS regeneration research, we need a detailed understanding of how regeneration is regulated on a cellular and molecular level in animal models with both high and low regenerative capacity. Understanding the regulatory programs necessary for robust ENS regeneration will pave the way for using neural regeneration as a therapeutic approach to treating ENS disorders. 
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                            - Award ID(s):
- 2143267
- PAR ID:
- 10385950
- Date Published:
- Journal Name:
- International Journal of Molecular Sciences
- Volume:
- 23
- Issue:
- 9
- ISSN:
- 1422-0067
- Page Range / eLocation ID:
- 4799
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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