All Publications

  • Enteric nervous system striped patterning and disease: unexplored pathophysiology. Cellular and molecular gastroenterology and hepatology Dershowitz, L. B., Kaltschmidt, J. A. 2024


    The enteric nervous system (ENS) controls gastrointestinal (GI) motility, and defects in ENS development underlie pediatric GI motility disorders. In disorders such as Hirschsprung's disease (HSCR), pediatric intestinal pseudo-obstruction (PIPO), and intestinal neuronal dysplasia type B (INDB), ENS structure is altered with noted decreased neuronal density in HSCR and reports of increased neuronal density in PIPO and INDB. The developmental origin of these structural deficits is not fully understood. Here, we review the current understanding of ENS development and pediatric GI motility disorders incorporating new data on ENS structure. In particular, emerging evidence demonstrates that enteric neurons are patterned into circumferential stripes along the longitudinal axis of the intestine during mouse and human development. This novel understanding of ENS structure proposes new questions about the pathophysiology of pediatric GI motility disorders. If the ENS is organized into stripes, could the observed changes in enteric neuron density in HSCR, PIPO, and INDB represent differences in the distribution of enteric neuronal stripes? Here, we review mechanisms of striped patterning from other biological systems and propose how defects in striped ENS patterning could explain structural deficits observed in pediatric GI motility disorders.

    View details for DOI 10.1016/j.jcmgh.2024.03.004

    View details for PubMedID 38479486

  • Spontaneous enteric nervous system activity precedes maturation of gastrointestinal motility. bioRxiv : the preprint server for biology Dershowitz, L. B., Garcia, H. B., Perley, A. S., Coleman, T. P., Kaltschmidt, J. A. 2023


    Spontaneous neuronal network activity is essential in development of central and peripheral circuits, yet whether this is a feature of enteric nervous system development has yet to be established. Using ex vivo gastrointestinal (GI) motility assays with unbiased computational analyses, we identify a previously unknown pattern of spontaneous neurogenic GI motility. We further show that this motility is driven by cholinergic signaling, which may inform GI pharmacology for preterm patients.

    View details for DOI 10.1101/2023.08.03.551847

    View details for PubMedID 37577464

    View details for PubMedCentralID PMC10418201

  • Anatomical and functional maturation of the mid-gestation human enteric nervous system. Nature communications Dershowitz, L. B., Li, L., Pasca, A. M., Kaltschmidt, J. A. 2023; 14 (1): 2680


    Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity.

    View details for DOI 10.1038/s41467-023-38293-z

    View details for PubMedID 37160892

    View details for PubMedCentralID PMC10170115

  • Regional cytoarchitecture of the adult and developing mouse enteric nervous system. Current biology : CB Hamnett, R., Dershowitz, L. B., Sampathkumar, V., Wang, Z., Gomez-Frittelli, J., De Andrade, V., Kasthuri, N., Druckmann, S., Kaltschmidt, J. A. 2022


    The organization and cellular composition of tissues are key determinants of their biological function. In the mammalian gastrointestinal (GI) tract, the enteric nervous system (ENS) intercalates between muscular and epithelial layers of the gut wall and can control GI function independent of central nervous system (CNS) input.1 As in the CNS, distinct regions of the GI tract are highly specialized and support diverse functions, yet the regional and spatial organization of the ENS remains poorly characterized.2 Cellular arrangements,3,4 circuit connectivity patterns,5,6 and diverse cell types7-9 are known to underpin ENS functional complexity and GI function, but enteric neurons are most typically described only as a uniform meshwork of interconnected ganglia. Here, we present a bird's eye view of the mouse ENS, describing its previously underappreciated cytoarchitecture and regional variation. We visually and computationally demonstrate that enteric neurons are organized in circumferential neuronal stripes. This organization emerges gradually during the perinatal period, with neuronal stripe formation in the small intestine (SI) preceding that in the colon. The width of neuronal stripes varies throughout the length of the GI tract, and distinct neuronal subtypes differentially populate specific regions of the GI tract, with stark contrasts between SI and colon as well as within subregions of each. This characterization provides a blueprint for future understanding of region-specific GI function and identifying ENS structural correlates of diverse GI disorders.

    View details for DOI 10.1016/j.cub.2022.08.030

    View details for PubMedID 36070775