Cell surface glycosylation regulation of stem cell fate decisions

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As the body forms during development, the cells that generate each organ receive a wide array of chemical, mechanical, and electrical signals that help them decide what types of mature cells to become. Some chemical and mechanical signals are conveyed by molecules, either freely-traveling or bound to a cell or a surface, that attach themselves to sensor molecules embedded on the outside of the developing cells. This cell outer surface is covered in sugars, but the role these sugars play in helping cells acquire and interpret the signals they receive during development remains poorly understood. The Principal Investigator's laboratory previously devised a novel way to study the cell surface, and used it to identify a new role for sugars in regulating brain formation. The present project will elucidate how the different types of sugars on the cell surface influence key decision points in brain development, shedding new light on crucial processes that affect brain formation and function. Since the cell surface components identified in these studies are also present on other organs besides the brain, the results of this research may reveal important general mechanisms through which cell surface sugars impact the development of many organs throughout the body. This project includes initiatives to encourage tomorrow’s scientists by providing a fun and engaging multi-disciplinary science experience for K-12 students through a community outreach program. These initiatives aim at encouraging and empowering young people to become scientists who can combine approaches from a variety of scientific disciplines to deepen our understanding of biological development. Undifferentiated cells encounter a variety of external signals that impact cell fate. External signals bind to plasma membrane proteins, and glycosylation plays a vital role in regulating membrane proteins by controlling their ligand affinity and cell surface residence time. Despite the importance of glycosylation, its role in cell fate decisions has been under-appreciated and under-studied. The goal of this project is to understand how glycosylation impacts neurogenic and astrogenic fate decisions of neural stem cells. Previous research devised a novel way to determine cell fate that also reflects cell surface glycosylation, and found that glycosylation regulates neural stem cell fate determination. Key enzymes [Mgat5 (associated with astrogenesis) and Mgat3 (associated with neurogenesis)] and distinct fate-specific patterns of cell surface proteins were also identified. The present research tests the general hypothesis that the balance of Mgat5 and Mgat3 activities is a critical determinant of fate potential, and regulates cell surface protein interactions with extracellular ligands. Three more specific hypotheses are tested using in-vivo and in-vitro experiments: (1) Mgat5 activity promotes astrogenesis, (2) Mgat3 prevents astrogenesis and promotes neurogenesis, (3) neurogenic and astrogenic cells differ in cell surface protein function due to the activities of Mgat5 and Mgat3. It is expected that these studies will reveal a crucial regulatory mechanism cells utilize to respond to the myriad extracellular signals that impact their fate choices.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.