How does a neural crest cell become a particular derivative?
Neural crest cells are a group of multipotent stem cell that migrate to various locations and give rise to many diverse cell types in the vertebrate body. The ENS arises from “vagal” neural crest stem cells that originate from the post-otic dorsal neural tube. Vagal neural crest cells are multipotent and can give rise to the outflow tract of the heart, enteric ganglia, sympathetic ganglia, as well as pigment cells of the skin. 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.
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 is to deepen our understanding of the signaling and genetic mechanisms that regulate early development and migration of vagal neural crest cells, thus expanding 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.
Currently, our research aims are to:
1 .Identify and functionally characterize the role of candidate microenvironmental factors during vagal neural crest migration and enteric neuron formation along the gut. 2. Construction of the signaling-level regulatory network that governs vagal neural crest development and neural crest migration during early ENS formation. 3. To understand how neural crest-derived cancers form from the vagal neural crest in vivo. 4. Relate ontogenesis of the ENS to disorders of the nervous system.
Currently funded by Cancer Prevention & Research Institute of Texas http://www.cprit.state.tx.us