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B.S., Rensselaer Polytechnic Institute – 2006
Thesis Advisor: Michael P. Matise, Ph.D.
Graduate Program in Cell and Developmental Biology
RWJMS Research Tower, Room V-10
Thursday, February 28, 2013
Sonic Hedgehog (Shh) is a secreted protein that plays a critical role in the development of the central nervous system. There are three tissue sources of Shh for spinal cord development: the node, notochord and floor plate (FP). Although prior studies have shown a critical role for Shh in patterned gene expression, the requirements of each individual Shh source have not been clearly defined. To address this, this study employed conditional mutagenesis in mice to selectively inactivate Shh in the FP while preserving Shh derived from the node and notochord. To disrupt the signal transduction pathway by compromising both the ligand and cell autonomous signal reception, Smo was also inactivated in neural tube progenitor cells. During early neural tube development, I found progenitor gene expression and patterning remained relatively unchanged suggesting a greater dependence on Shh derived from the node and notochord, consistent with prior studies. However during gliogenesis, Shh from the FP is required to specify ventrally derived oligodendrocyte cell fates via the repression of Gli3 repressors. Yet, despite the early decrease in oligodendrocyte precursors, I find that oligodendrocytes eventually recover to wild type levels in post natal tissues. Interestingly, my study also found a role for Shh signaling in the expression of astroctye associated genes, raising the possibility of a link between hedgehog signaling and astrocyte development. Finally, I also found during late embryogenesis, hedgehog signaling is required for the proper maintenance of the spinal cord ventricular zone and the eventual formation of the adult ependymal zone. Taken together, the results demonstrate a specific and critical requirement for floor plate derived Shh in regulating the specification and differentiation of glial and ependymal cells in the spinal cord.