Origins of Ret Signaling in Development of the Insect Gut Nervous System: A Model for Enteric Nervous System Development
AuthorMyers, Logan G.
Biochemistry and Molecular Biology
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Understanding the evolutionary origins of neurotrophic signaling guiding the formation and upkeep of the central and peripheral nervous systems (CNS/PNS), can offer insights into the basis of development and congenital diseases affecting those systems. In humans, fatal disorders caused by disturbed formation of the enteric nervous system (ENS) of the gut such as Hirschsprung’s disease as well as degeneration of dopamine neuron populations in Parkinson’s disease are multigenic. In short, these diseases have a confounding collection of genetic causes. Many years of research have provided scientists with numerous targets for treatment, however it is difficult to find new and investigate proposed genetic interactions due to research limitations of genetic studies. It is necessary to refine systems allowing genes and their products, involved in nervous system development, to be studied more easily and efficiently. Uncovering ancestral genes within families of trophic factors may also be key to finding novel targets to treat or stop the progression of these diseases.Development of the ENS in vertebrates, often referred to as the “second brain”, relies heavily on signaling from the Ret receptor tyrosine kinase (RTK). Mutations in Ret and/or its coreceptor and GDNF ligand lead to a condition characterized by lack of neural innervation in terminal portions of the gastrointestinal tract and loss of normal gut function in affected areas. Instances of this condition where mutations within genes of the Ret signaling complex cannot be identified leave investigators with questions about the genetic profile of the problem. Laboratories have established mouse and zebrafish models to study ENS development, but limitations arise in the degree to which the underlying genetics can be manipulated for study. It is important to have a system that can be used for genetic screens as well as system-based treatment studies that the current models cannot provide. This dissertation will describe such a system.The invertebrate fruit fly Drosophila melanogaster is a genetically accessible model system being used for studies of CNS and PNS development. Novel discoveries have been made in the fly regarding the cellular and molecular mechanisms guiding brain formation. Drosophila have a compact gut nervous system that we can use to study mechanisms guiding ENS formation. We have organized a genetic toolkit to study this system and examined the role that the fly Ret homolog has on the formation of its enteric neurons. We have found that loss of Ret signaling in the fly leads to defects in fly gut nervous system development and an equivalent condition to that seen in vertebrate models. Defects in embryonic enteric neurons lead to aberrant architecture of larval gut neurons. These flaws subsequently cause feeding defects and increased larval mortality. Additionally, we have evidence for the other members of the Ret signaling complex in the fly. This work shows that the protein Maverick functions as a proto-GDNF in invertebrates via a Gfrl co-receptor. Maverick is the earliest identified ligand for the RTK conserved from early invertebrates all the way to humans.The results of this dissertation establish the fruit fly as a genetically accessible model to study the development of the ENS. This model will allow us to dissect the genetics of Hirschsprung’s disease and related disorders. Genetic knockouts and transgenic approaches can be used to discover new relationships between genes that can add to our understanding of diseases affecting nervous systems. This work provides the basis for screens to identify novel targets to neural diseases affecting people around the world. Drug targets can also be quickly identified in this model thanks to feeding studies in adult animals. This is becoming more intriguing with new relationships being found between the CNS and the ENS in cases of Parkinson’s and other neurodegenerative disorders. Future work will contribute to treatment of congenital diseases affecting the nervous system without the need for current invasive surgeries and ineffective long-term drug treatments.