Neural Crest Cell Diversification
Neural crest cells are stem cells that migrate to various locations and give rise to diverse and fundamental cell types in the vertebrate body–including craniofacial tissues, cardiac cells and peripheral nervous system. Neural crest stem cells originate from the dorsal neural tube, a transient structure during development that will eventually give rise to the central nervous system. Some of the neural crest cells, called "vagal" neural crest cells, eventually can give rise to cells of the outflow tract of the heart, enteric peripheral ganglia, sympathetic ganglia, thymic connective tissue, as well as pigment cells of the skin.
What dictates whether neural crest will give rise to ganglia or other derivatives, such as pigment cells or connective tissues, remains elusive. To address this challenge, we study what regulates neural crest cell delineation, in the zebrafish embryo, a robust vertebrate model.
Towards that end, and begin shedding light on neural crest differentiation, we have undertaken studies on neural crest diversification in zebrafish using single-cell transcriptomics (Howard, Baker et al., 2021), and discovered dozens of transcriptionally-distinct neural crest-derived cellular subpopulations, greatly expanding the field's basic understanding of neural crest cell development. From these populations, we have uncovered previously unappreciated signatures of various genes, including those encoding transcription factors, implicating them in diversification of the vagal neural crest derivatives, including the ENS. Ongoing studies are building upon our recent single-cell discoveries in the lab right now.
Enteric Nervous System Differentiation
The ENS is largely derived from the neural crest. The main constituents of the ENS are hundreds of thousands of neurons and glia embedded within the walls of the gut. The ENS exhibits diverse enteric neuron subtypes and glial cells, which together regulates gut peristalsis, water balance and hormone secretions. The number of neurons found within the ENS rivals the numbers of those found in the spinal cord, causing it to also be known as "the second brain."
During zebrafish embryonic development, enteric neural crest cells migrate into the primitive gut as two migratory chains, surround the gut tube, and turn into neurons by the 5th day in development in order to form the ENS. Zebrafish offer a simplified model to study ENS development. In our lab, we seek to understand how the ENS differentiates from the neural crest.
First main branch of our ENS work: We investigate how factors, such as Vitamin A-derived Retinoic Acid and other microenvironmental signaling factors, interact with neural crest cells and gut tissues to orchestrate early ENS tissue patterning. In addition, we are taking an unbiased approach by leveraging our single-cell datasets, to define the functional role of under-described pathways that are expressed during early ENS formation. Finally, we also are interested in determining if certain transcription factor families regulate molecular, cellular and tissue-level events during early ENS development.
Second main branch of our ENS work: We currently leverage whole animal time-lapse live imaging and single cell tracking experiments to resolve the complex emergence of enteric neurons in the zebrafish gut, as shown on video left.
Our recent study is out now https://doi.org/10.1242/dev.200668, in which we observed that enteric neural crest cells couple proliferation, migration speed, and cell density, to ensure proper gut tube colonization and timing of enteric neuron differentiation.