Enteric Nervous System Formation and Neural Crest Cell Diversification
We utilize various experimental approaches to quantitatively determine how the vertebrate embryo sculpts the enteric nervous system from neural crest stem cells. To this end, we investigate which genetic programs dictate neural crest transformation into functional enteric neuron types, the factors that control their proliferative expansion and their transformation into abnormal cells during pathological states, including cancer. We leverage a combination of confocal time-lapse imaging, classical developmental biology assays, genetic perturbations, bulk and single-cell RNA-seq transcriptomics, bioinformatics and computational methods.
Neural crest cells are stem cells that migrate to various locations and give rise to many diverse and fundamental cell types in the vertebrate body. The ENS largely arises from “vagal” neural crest stem cells that originate from the post-otic dorsal neural tube, a transient structure during development that will give rise to the central nervous system. Vagal neural crest cells eventually can give rise to the cells of the outflow tract of the heart, enteric ganglia, sympathetic ganglia, thymic connective tissue, as well as pigment cells of the skin. Therefore, they are fundamental to life. To become enteric ganglia during development, vagal neural crest migrate ventrally from the neural tube and enter the primitive foregut tissue. They then migrate along the rostrocaudal extent of the gut in response to microenvironmental signaling cues to until they eventually reach the hindgut. These enteric neural crest cells (ENC) eventually give rise to a diverse array of neurons and glia that form the enteric ganglia. What dictates whether vagal neural crest will give rise to enteric ganglia or other derivatives, such as pigment cells, remains elusive.To address this lack of knowledge, we study what regulates vagal neural crest cell delineationprimarily using transcriptomics and hypothesis-based experiments in the zebrafish embryo.
Relevance to Human Health: Understanding the genetic programs and cellular interactions that drive stem cells to form the enteric nervous system is of crucial concern. Because improper neural crest development leads to developmental anomalies such as Hirschsprung disease (colonic aganglionosis), and neural crest-derived cancers, such as Melanoma and Neuroblastoma, there has been great interest in understanding the migration and differentiation of vagal neural crest cells. Hirschsprung disease is characterized by a paucity of ganglia along variable lengths of the gut, with colonic aganglionosis being the most common form, occurring every 1 in 5000 births.. The current treatment for this pediatric developmental defect is surgical resection of the aganglionic intestinal segment--however eventual outcomes of patients varies greatly and most exhibit functional enteric defects throughout life--highlighting the need for alternative treatments and understanding the ontogeny of the disorder.
Melanoma and Neuroblastoma are neural crest-derived cancers affecting adults and children alike throughout the world. It is hypothesized that several genetic mutations in neural crest cell lineages are the basis for the formation of these cancers, however the signaling landscape conducive to formation of melanoma and neuroblastoma are not entirely known.
The goal of our research program is to deepen understanding of the microenvironmental, signaling and genetic mechanisms that regulate early development, migration and differentiation of vagal neural crest cells. Using this as an avenue of exploration, it is our hope that this will expand our knowledge of both normal and abnormal enteric nervous system development--as well as fundamental mechanisms underlying neural crest lineage segregation. In addition, we focus on investigating how neural crest-derived cancers are born and metastasize, using zebrafish as a robust model organism.