Induction and Maintenance of Neural Progenitors

Georgetown University, Washington DC

Investigators

Abstract

The first step in the formation of the central nervous system (i.e. brain and spinal cord) is the induction of a plate of cells on one side of the developing embryo. This plate consists of proliferating neural stem cells that differentiate and form all of the neurons and glia of the brain and spinal cord. To create a brain of the correct size and organization, the neural stem cells must be tightly regulated such that they replenish themselves through cell division, and then differentiate into neurons at the right time during development. Many of the signals required to induce neural stem cell formation and to direct neuron formation are known, however how the regulatory signals are relayed, interpreted and coordinated to form a complex, centralized nervous system is unknown. To determine how these signals induce and instruct neural stem cells, the process will be compared in both a simple (marine acorn worm) and complex (frog) organism. The acorn worm and frog have similarly structured nervous systems but use unique routes during development to reach the same end. Thus, comparison of the induction and segregation of their nervous systems allows for the identification of the essential components and changes that evolved to allow for the development of the complex vertebrate brain. These studies are fundamental for explaining how multiple signals are integrated and decoded to regulate stem cells and to form a highly structured organ. These studies will provide numerous training opportunities for high school, undergraduate and graduate students including members of underrepresented groups in science and are essential to the development of the acorn worm as a model organism to study the development of the brain and other organs. The specification of neuroectoderm and the maintenance of a neural progenitor population are tightly regulated and fundamental to the development of the central nervous system. While many of the signals (BMP and FGF) and transcription factors involved in neurogenesis are known, the mechanisms by which signals drive changes in gene expression and how the signals are coordinated to maintain a balance of proliferating stem cells and differentiating neurons are not well defined. This project examines the role of FGF and BMP signaling in neural progenitor induction, maintenance and segregation in the chordate Xenopus laevis and the hemichordate Saccoglossus kowalevskii. The molecular and embryological tools in Xenopus enable identification of the molecular mechanisms downstream of BMP signaling that induce the nervous system, and the identification of the roles of FGF in the induction and maintenance of progenitors. The Xenopus studies combined with analysis of the formation of the nervous system in Saccoglossus allows for the identification of conserved and novel regulatory themes in the specification and segregation of neural cells. The unique neural organization and development of Saccoglossus provides a unique opportunity to address a major question in developmental biology - How do changes at the molecular level drive significant morphological changes? This critical deuterostome dataset will broaden the phylogenetic perspective and provide insight into the evolutionary history of the development of the nervous system. These studies will provide numerous training opportunities for high school, undergraduate and graduate students including members of underrepresented groups in science and the focus on technique development in Saccoglossus is essential to its development as a model organism to study neural development.