Developmental Neurogenesis and its Impact on Disease States

Goals

1. Determine how two populations of stem cells cooperatively migrate and differentiate into olfactory sensory neurons in vivo.
2. Understand how olfactory neuroregeneration is maintained throughout adulthood and why it is disrupted in neurodegenerative disorders.
3. Quantitatively compare neural crest and neural crest-derived cancer cell behavior in vivo to uncover druggable targets that modulate cancer survival or metastasis.
4. Establish new connections between embryonic sympathetic neurogenesis and the manifestation of atrial fibrillation in adults.

Overview

We apply high-resolution live imaging of vertebrate model organisms to quantitatively study embryonic development, adult regeneration, and pediatric cancer, with a focus on how 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 olfactory system in zebrafish as our main experimental canvas, with the complementary use of other model organisms as needed. Our work is highly interdisciplinary and benefits from 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 major 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 revealed a contribution of the cranial neural crest to olfactory sensory neurons (an unexpected fate) via precisely orchestrated cell migration and differentiation. Now, we are determining how two tightly intermingled populations, neural crest- and placode-derived progenitors, communicate and assemble a complex neuronal structure. Additionally, we are investigating how newly identified developmental pathways influence adult neuroregeneration post-injury and in neurodegenerative disease states, i.e. how stem cells enter the cell cycle and differentiate to form new neurons at the right time and place in adults. Finally, we are applying our developmental neuroscience expertise to shed light on the behavior of neural crest-derived pediatric cancer cells, with the goal of discovering inhibitors of metastasis that could improve patient outcomes.

In sum, 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 in vivo. Data are obtained via molecular, genetic, and physical (laser-induced) perturbation, combined with high-resolution imaging, quantitative analysis, and computational modeling. We aim to 1) manipulate the differentiation of stem cells and cancer cells into neurons in vivo; 2) understand the integration and function of newly differentiated neurons across multiple organs and disease states.