Neurogenesis in the enteric nervous system: uncovering neurogenic potential through inducible models
Collins, Malie Kawila
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Great strides have been made with regard to neurogenesis in the enteric nervous system (ENS), rapidly following in the wake of recent revelations about the neurogenic properties of the central nervous system (CNS). As the ENS is more exposed, highly complex, and vulnerable to a variety of developmental, acquired, and multisystemic disorders, there is a sense of urgency for studies to address the potential within the gut to restore neurons that are injured or lost. It is the intricacies of the ENS and yet unclear relationships between agonists and embryonic precursors that have made demonstrating the arrival of new neurons in mature gut difficult under steady-state conditions. This thesis demonstrates that inducible models of a wide range of insults to the gut have yielded crucial information about ENS neurogenesis, while in vivo experimentation under steady-state conditions has proven inconsistent. Specifically, the signaling pathways of Ret and PTEN have revealed the existence of a ‘natural block’ that normally regulates neurogenesis and keeps proliferation well controlled. Furthermore, the overwhelming effects of serotonin agonism on neuron density in response to injury have uncovered an essential role of neuronal transdifferentiation by enteric glial cells that extends beyond what was once understood to be a largely homeostatic role. The influence of extrinsic innervation of the gut will also be explored, physiology of which is important for both the utility of gut microbiota and the role of Schwann cell progenitors in the development of the ENS. Therefore, this thesis will outline ENS organization and function, as well as describe common pathologies that serve as the foundation upon which neurogenesis is investigated. Critical inducible models to which chemical and molecular agonists are applied will be examined in detail, as it is through these models that therapeutics and biomedical engineering can be optimized in order to correct the pathophysiology of enteric neuropathies that as of now are still treated with surgical intervention.