Molecular control of autonomic nervous system cell types

Autonomic nervous system (ANS) provides essential control of our body functions, ranging from rest-and-digest to fight-or-flight responses. It is also a source of numerous pathologies. Although the identification of transcriptional states based on the single cell transcriptomics mapping already provided new descriptive insights into developmental aspects of different sympathetic, oxygen sensing carotid and chromaffin cells, the discoveries of functionally-validated molecular mechanisms driving diversification, identity and progression of multiple autonomic cell types lag behind and currently represent the major knowledge gap. In this project, we will fill in this knowledge gap by performing a multiplexed functional screen of transcription factors and receptor molecules in different combinations, to find those molecules, which drive the identity of terminal subtypes of chromaffin, oxygen sensing carotid cells and ANS neurons. We will also screen transcription factors and receptor molecules that are associated with decision-making during fate selection and transitions between progenitor states. This project will result in functional identity codes that might be used for generating diverse autonomic nervous system cell types in vitro and in vivo, as well as factors driving transitions and fate selection towards them. Overall, we plan to explain how specific functional genetic modules are combined to build specific subtypes of ANS neurons and neuroendocrine cells. This will improve our understanding of a nature of multiple ANS dysfunctions related, for instance, to unwanted adrenergic-to-cholinergic phenotype switching in cardiac ganglia of elderly arrhythmia patients, or to insufficient ANS function in one of the key body organs. Furthermore, the cancer field might potentially benefit from these results by better understanding cell phenotypes in ANS tumors, which might assist identification of cell of origin or onco-fetal transformations in tumors.