Goals: 1. Determine how two populations of stem cells cooperatively migrate and differentiate into olfactory sensory neurons in vivo. 2. Understand how olfactory neuronal turnover is maintained throughout adulthood and disrupted in neurodegenerative disorders. 3. Compare neural crest and neural crest-derived cancer cell behavior in vivo to uncover new druggable targets that inhibit metastasis.
Overview: We apply high-resolution live imaging of vertebrate model organisms to quantitatively study embryonic development and pediatric cancer, with a focus on how neural crest stem cells migrate long distances (akin to cancer metastasis) and differentiate into a variety of specialized cell types. Our in vivo, system-wide approach is inspired by challenging long-term goals of biomedical research, namely to prevent and/or repair human birth defects and pediatric cancer progression. To achieve these goals, we must first understand how vertebrate embryonic development goes awry, which, in turn, requires understanding how development occurs correctly in its natural environment. Therefore, we are elucidating the multicellular dynamics that drive stem cell migration and differentiation into neurons and that may also contribute to cancer cell migration and survival.We take advantage of easily accessed and manipulated neural crest migratory streams and the developing olfactory system in zebrafish as our combined experimental canvas, with the occasional use of other model organisms. Much of our work is highly interdisciplinary and benefits from synergistic interactions with other research groups (list of collaborators below). Details: By revealing the origins of vertebrate sensory neurons and the molecular and cellular processes driving the remarkable transformation from stem cell to neuron, we can better comprehend general mechanisms of neurogenesis and the potential for regeneration. Olfactory sensory neurons are particularly unique in their regenerative capacity throughout adulthood, with a completely new set of neurons present in the human nose almost every month. Thus, there is significant translational value in understanding the origins and differentiation pathways of these unusual derivatives.
The neural crest is a highly migratory, multipotent stem cell population that contributes to a variety of tissues in the developing embryo - including a significant portion of the peripheral nervous system - and is critically important for craniofacial development as a whole. In addition, neural crest-derived cells can give rise to neuroblastoma, the most common type of cancer in the first year of human life. Intriguingly, neuroblastoma shares many common features - both genetic and phenotypic - with the neural crest, and over 60% of neuroblastomas metastasize, with behavior reminiscent of neural crest migration.
Our previous work has revealed a novel contribution of the cranial neural crest to olfactory sensory neurons (an unexpected fate as opposed to the expected formation of craniofacial mesenchyme) via dynamic, precisely orchestrated cell migration and differentiation (Saxena et al., eLife 2013). Now, we aim to uncover the molecular, cellular, and system-wide changes underlying this intricate process, including how two tightly intermingled populations, neural crest- and placode-derived progenitors, communicate and assemble during olfactory neurogenesis. Additionally, we are investigating the relevance of identified developmental pathways in adult neuroregeneration by inflicting injury and tracking recovery via live imaging and analysis of adult stem cell behavior. We are examining where stem cells reside and how they reenter the cell cycle and differentiate to form new neurons. We are also applying our quantitative approaches to shed light on the behavior of neural crest-derived cancer cells, with the goal of discovering new inhibitors of cancer metastasis. Given the poor clinical prognosis post-metastasis, inhibiting malignant cells' migration has significant potential to help improve patient outcomes.
In sum, rather than study cells in vitro where context is missing, we take advantage of easily manipulated live vertebrates to produce a system-wide overview of how cells interact with and influence each other over space and time. Data are obtained via molecular, genetic, and physical (laser-induced) perturbation combined with high-resolution imaging, quantitative analysis, and computational modeling. By studying developmental, regenerative, and cancer biology completely in vivo, we aim to uncover new insights into how neurons are formed, how complex neuronal networks are assembled and maintained, and how neural crest migration and cancer metastasis are commonly regulated.
