Signaling mechanisms underlying neural crest cell fate decisions

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The neural crest contributes a wide variety of cell types to the human face, giving rise to teeth, melanocytes, the craniofacial skeleton, and the peripheral nervous system. The diversification strategies used by the neural crest are still elusive, but seem to be highly sensitive to genetic perturbations because heritable diseases frequently disrupt neural crest development, which can impact craniofacial growth. Thus, clarifying how cell interactions bias neural crest cell fates could reveal mechanisms of disease progression, many of which remain obscure. To perform a systematic characterization of neural crest lineages and their developmental regulation by cell signaling, we have built upon our recent breakthroughs in single-cell transcriptomic analysis to include viral gene delivery for functional interrogation. Using barcode-based clonal lineage tracing and high- throughput genetic perturbations in vivo via ultrasound-guided injections of lentivirus into the forming cranial neural crest region, we will map how cell lineages interact and diversify to build the face. Based on our preliminary data, we hypothesize that neural crest cells utilize collective multipotency, and communicate via signaling interactions in the dorsal neural tube that balances molecular biasing of early neural crest cells towards fates in correct proportions. We will test this hypothesis by functional experiments targeting receptors and ligands in neural crest subpopulations, with special emphasis on genes that when mutated, can result in pathology. By assembling a global collaboration of experts in advanced imaging techniques, single-cell transcriptomics, and mammalian genetics, we will determine the disease mechanisms underlying failures in facial development, and in doing so, contribute valuable datasets for the craniofacial and neural crest biology communities. Successful completion of our research plan will illuminate potential avenues to manipulate the behavior of stem cells at the population-wide scale, and reveal how cell fate choices could be manipulated in specific locations in vivo to generate skeletal shape and form. This three- year postdoctoral training plan is an excellent opportunity for the candidate to train at a world-renowned medical research environment, while gaining a unique combination of skills, background and network that will make a clear path towards scientific independence.