Barsh, G. R. | Search bioRxiv

bioRxiv2026

Abnormal enteric nervous system organization and gastrointestinal motility in mice with valproic acid-induced neural tube defects

BackgroundNeurogenic bowel is a major cause of morbidity in patients affected by neural tube defects (NTDs) such as spina bifida, but the underlying reasons for bowel dysfunction are unknown. An absolute requirement for gastrointestinal (GI) motility is the enteric nervous system (ENS) located within the walls of the GI tract. Enteric neurons coalesce into circumferential stripes throughout embryonic and early postnatal development, and this gradual organization of the ENS into enteric neuronal stripes correlates with the emergence of neurogenic GI motility. We hypothesized that NTDs are associated with changes in ENS organization that correlate with specific GI motility defects. MethodsWe used prenatal valproic acid (VPA) exposure as a model for NTDs in embryonic mice. We used immunohistochemistry, high resolution confocal imaging, and ex vivo motility assays to assess enteric neuronal stripes and gastrointestinal motility in embryos with a VPA-induced neural tube defect. Key resultsGI tracts from embryos with a VPA-induced NTD contain blood. Structurally, the enteric neuronal stripes are thinner with a narrower interstripe distance, leading to an increased number of stripes. Functionally, GI motility is abnormal, with increased contraction frequency and increased length of contractile segments. Conclusions and inferencesENS organization and GI motility are disrupted in mouse embryos with a VPA-induced NTD. This has important implications for our understanding of neurogenic bowel in central nervous system diseases such as spina bifida. Key Points- VPA exposure is a reliable model of neural tube defects with variable intralitter susceptibility - Embryos with a VPA-induced neural tube defect have blood in the amniotic sac and within the lumen of the gastrointestinal tract - Enteric nervous system organization is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, with thinner enteric neuronal stripes and narrower interstripe distance - Ex vivo gastrointestinal motility is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, including increased contraction frequency and increased length of the contractile segment

neuroscience↗

bioRxiv2019

Retinoic acid organizes the vagus motor topographic map via spatiotemporal regulation of Hgf/Met signaling

The topographic map, in which the positions of neuron cell bodies correspond with the positions of their synaptic targets, is a major organizational motif in the nervous system. To understand how topographic axon targeting is controlled during development, we examine the mechanism underlying topographic innervation of the pharyngeal arches by the vagus motor nerve in zebrafish. We reveal that Retinoic Acid organizes the topographic map by specifying anterior-posterior identity in post-mitotic vagus motor neurons. We then show that chemoattractant signaling between hepatocyte growth factor (Hgf) and the Met receptor is required for pharyngeal arch innervation by the vagus motor nerve. Finally, we find that Retinoic Acid controls the spatiotemporal dynamics of Hgf/Met signaling to coordinate axon targeting with the developmental progression of the pharyngeal arches and show that experimentally altering the timing of Hgf/Met signaling is sufficient to redirect axon targeting and disrupt the topographic map. These findings establish a new mechanism of topographic map development in which regulation of chemoattractant signaling in both space and time guides axon targeting.

developmental biology↗