The enteric nervous system (ENS) is an extensive network of neural crest-derived neurons and glia that control bowel motility and other vital aspects of bowel function such as absorption and secretion. To perform these functions, the ENS utilizes more than 20 neuron types and relies on an extraordinary level of neurotransmitter diversity (1). When the ENS does not develop or function properly, symptoms include constipation, distension, and abdominal pain, which impair quality of life and cause life-threatening complications. Recently, we began investigating the role of BAP1 in ENS development and function using a mouse strain with a conditional deletion of Bap1 induced by Cre-recombinase under the control of the tyrosinase promotor. Tyrosinase is expressed in the majority of migrating neural crest cells. Previously, BAP1 has been linked to decreased expression of genes involved in neural crest migration(2). BAP1 is an epigenetic modifier involved in regulating gene expression through chromatin remodeling and deubiquitylation (3-6). Currently, we hypothesize that Bap1 is involved in regulating genes important for neuronal development and function.

Loss of BAP1 causes mice to experience failure to thrive and die at 3-4 weeks of age with megacolon. This is consistent with Hirschsprung Disease, where neurons fail to colonize the distal colon. However, loss of BAP1 in ~96% of neural crest cells demonstrates complete migration of the enteric neural crest and normal ENS density at birth in both the submucosal and myenteric plexuses throughout the bowel. Nevertheless, loss of BAP1 in the tyrosinase lineage results in decreased neuron density in the myenteric and submucosal plexuses at P15. The proportion of NOS1+ neurons to total neurons remains the same, suggestng NOS1+ neurons are also lost. There is a significant decrease in the percent of ENS neurons that are Tyr-Cre+ in Tyr-Cre+; Bap1 fl/fl mice, indicating loss of Tyr-Cre+ neurons is responsible for the decrease in total neuron density. Unsurprisingly in vivo and in vitro assays show slower motility in small and large bowel of TyrCre+; Bap1 fl/fl mice at P15. To determine the cause of the neuronal loss, we aim to characterize expression abnormalities in neuronal populations by collecting single cell-RNA Seq data from P5 TyrCre+; Bap1 fl/fl and WT mice.