CAREER: Molecular control of differentiation in the enteric nervous system

Michigan State University, East Lansing MI

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). The enteric nervous system (ENS) – the “brain in the gut” – regulates important gastrointestinal tract functions such as digestion and nutrient uptake. To fulfill this role, a complex network of specific cell types – nerve cells and glial cells – need to be assembled during development. The genetic factors that regulate the generation of these different cell types and the circuits they form during development are poorly understood. It is also not known if the circuits in distinct regions of the gut (for example, the stomach and intestine), are constructed using different signals, or if the same developmental signals are used along the whole length of the gut. This project will provide fundamental insights into how the enteric nervous system develops, and the interactions between the neural circuits of the gut and surrounding tissues. Understanding how gut neural cell types get generated is also essential for a better comprehension of how these nerve cells regulate gut physiology and function. In addition to its scientific goals, this project will also provide extensive, hands-on research experiences for undergraduate students through 1) a new research-intensive undergraduate course on genome editing and 2) organized research experiences for undergraduates starting in their first year. Additional training opportunities are provided for graduate students and postdoctoral researchers, as well as public outreach activities that aim to increase scientific literacy by showcasing the advantages of zebrafish research in neuroscience via interactive booths at regional science fairs. The ENS is the largest part of the peripheral nervous system providing the intrinsic innervation of the gut. Despite the critical role of the ENS for gut development and function, there is a significant gap in knowledge regarding the genes and fundamental principles that control ENS neuronal development. Each gut subdivision has specific functions – accordingly, the ENS also shows regional molecular and cellular differences along the gut. A fundamental yet unexamined question that remains is the degree to which ENS neurogenesis is regulated by region-specific programs within each gut subdivision. Addressing this question is essential for a complete understanding of the core principles that underlie ENS neurogenesis, as well as a better understanding of how the ENS develops in concert with surrounding gut cells. This project will determine region-specific gene activities and their regulatory programs in sets of experiments. The first set will elucidate molecular mechanisms that control region-specific ENS neurogenesis. The second set will identify region-specific regulatory programs using epigenomic and transcriptomic profiling to detect and functionally test regulatory components. The third set will discover the extent to which region-specific regulatory programs control ENS neurogenesis by using a CRISPR genome editing pipeline to assess the region-specific function of selected transcription factor genes. This work will significantly expand knowledge about the genes and regulatory programs that control ENS neurogenesis, as well as provide research experiences for undergraduates through developing a new CRISPR genome editing course and independent scientific research in the PI’s lab. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.