Novel Insights into the Genetic and Environmental Determinants of Enteric Nervous System Biology

The enteric nervous system (ENS) is a complex network of neurons and glia that resides within the bowel wall. It rivals the spinal cord in complexity and regulates crucial bowel functions like gastrointestinal motility. Dysfunction of the ENS, also called enteric neuropathy, can cause growth failure, abdominal distention, and, in some individuals, sepsis and early death. Hirschsprung disease, a developmental enteric neuropathy where the ENS is missing from the distal bowel, can be treated with surgical removal of the affected bowel segment. However, debilitating bowel problems including dysmotility persist in a subset of patients. Treatment options of chronic intestinal pseudo-obstruction (CIPO) are even more limited and mostly symptomatic. In CIPO, the ENS develops along the length of the bowel, but bowel motility is compromised. Due to the dearth of options, the scientific community is actively trying to develop effective therapeutic options to improve enteric neuropathy-related symptoms. Bowel problems in CIPO and Hirschsprung disease post-surgery have been attributed to loss or dysfunction of subtypes of enteric neurons. Ideally, curative treatment would involve postnatal replacement of the defective ENS or supplementation of these missing ENS cell types. Recently developed in vitro differentiation protocols that convert human pluripotent stem cells into enteric neurons and glia have made stem cell therapy an enticing avenue to pursue. However, we still do not sufficiently understand the nuances of enteric neuron subtype fate decisions to direct differentiation of enteric neuron precursors into specific neuron subtypes. In chapter 2, I describe our work characterizing the differential expression of transcriptional regulators in enteric neuron subtypes during embryonic development and in the adult colonic ENS. We show that the transcription factor Tbx3 is required for the development of a normal complement of nitrergic neurons in the neonatal ENS. In chapter 3, I describe our work towards designing a high throughput screen that will allow us to determine whether transcriptional regulators affect differentiation into cholinergic versus nitrergic enteric neuron subtypes. In chapter 4, I describe exciting new work that indicates that postnatal treatment of distal colon lacking an enteric nervous system with the neurotrophic factor GDNF can re-grow a normal, functional ENS in mice. This discovery may lay the foundation for the development of adjunct, non-invasive therapeutic options for the treatment of Hirschsprung disease. Lastly, in chapter 5, I introduce work towards understanding the function of the epigenetic regulator Bap1 in enteric nervous system development and postnatal maintenance