The Role of FGF Signaling in the Regulation of Pluripotency and Neural Crest FormationPublic Deposited
The neural crest is a unique, vertebrate specific stem cell population that gives rise to a diverse set of derivatives in the embryo, including sensory neurons, glial cells, melanocytes, and craniofacial structures such as cartilage, bone, and connective tissue. Unlike other multipotent stem cell populations present at this time, neural crest stem cells are not restricted to a specific germ layer, and they retain their pluripotent potential while other neighboring cells are becoming further restricted. How neural crest cells evade the push to become lineage restricted, however, is unclear. Thus, studies of this important cell population will provide insight into the molecular underpinnings of stem cell potency and advance our understanding of how cell fate decisions are regulated in the early embryo. In this thesis, I explore how stem cell attributes are controlled in pluripotent blastula stem cells and investigate how this relates to the mechanism by which neural crest cells retain their stemness during embryonic development. I found that FGF signaling is required for proper blastula-stage gene expression and the appropriate lineage restriction of these cells, and that FGF signals execute context-dependent effects by differentially activating two different downstream signaling cascades. For instance, the MAPK cascade is active in blastula stem cells and is required for the pluripotency of these cells, while the PI3K/Akt cascade is required for the transit of cells to a subset of lineage restricted cell states. I further discovered that neural crest stem cells retain high MAPK:low Akt activity, and that this is required for proper establishment of the neural crest. In order to address how this differential cascade activation is achieved, I investigated the role of signaling adaptors and found that levels of the adaptor proteins Sos1 and Gab1 are critically important for activation of the MAPK and PI3K/Akt signaling cascades. Additionally, I discovered that Sos1 is required for proper embryonic patterning and is essential for blastula-stage pluripotency. Together, my findings detail the different roles of FGF signals throughout early embryonic patterning and demonstrate a novel mechanism by which this pathway elicits context-specific effects during cell fate determination.
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