THE ROLE OF TCF7L2 IN THE GENERATION OF OLIGODENDROCYTES DURING DEVELOPMENT A Project

I certify that this student has met the requirements for format contained in the University format manual, and that this project is suitable for shelving in the Library and credit is to be awarded for the project. One of the major obstacles to myelin repair in multiple sclerosis is the failure of endogenous oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes (OLs). Transcription factor 7-like 2 (TCF7l2), also known as TCF4, is a transcriptional effector that mediates canonical Wnt/β-catenin signaling in Wnt-responsive cells. The role of TCF7l2 in the generation of OPCs from neural stem cells (NSCs) is unknown, although canonical Wnt/β-catenin signaling has been shown to inhibit NSCs from generating OPCs. To study the role of TCF7l2 in OPC differentiation, we conditionally ablated TCF7l2 in Olig2+ cells and Cnpase+ cells (neural stem cells and OPCs) in the developing mouse spinal cord. We analyzed embryonic spinal cord tissues for changes in the OPC population and found decreased OPCs in TCF7l2 knockout mice. We also investigated whether TCF7l2 exerts its effects in OLs in a Wnt-independent manner during neural development using the Wnt reporter mouse strain BAT-lacZ. Our vi data show that TCF7l2 deletion does not affect Wnt/β-catenin signaling, indicating that TCF7l2's effects in OPC generation is Wnt-independent. Contrary to previous findings, our data show that TCF7l2 in fact promotes oligodendrogenesis, and that it does so independent of the Wnt/β-catenin pathway. _______________________ Date vii ACKNOWLEDGEMENTS I would first like to thank David Pleasure for his invaluable mentorship and guidance. I consider myself lucky to have had the chance to learn from you. I would also like to thank Fuzheng Guo for the many opportunities he has given me to grow as a scientist. Thank you, Fuzheng, for challenging me to think critically and for encouraging me to have confidence in myself.