| During development, the neural tube is patterned by a complex network of cross-regulatory signals that eventually result in the differentiation of all of the specific cell types necessary for the correct functioning of an adult nervous system, each in their appropriate position in the brain, spinal cord, or periphery. Sonic hedgehog (Shh) is a protein that signals from the ventral aspect of the neural tube and is required for the specification of the domains of many ventral and dorsal neural cell types. Far from accomplishing this feat on its own, Shh is influenced by a variety of other factors in this process. This dissertation clarifies some of these influences. In the first part of my research, I used constructs that modulate post-translational processing of Shh in order to investigate the importance of the native cholesterol attachment for Shh signaling. I found that removing the endogenous cholesterol modification or replacing it with other hydrophobic molecules prevented the Shh from establishing a gradient of response in neural tissue. In the second part of my research, I investigated two factors that influence the effects of Shh in cells receiving a Shh signal. I found that signaling through the Wnt/β-catenin pathway that is active in the dorsal aspect of the neural tube antagonized the Shh response in neural tissue, likely participating in a negative feedback loop to refine the dorsal aspect of Shh signaling. In contrast, the cyclic nucleotide cGMP enhanced the response to Shh, demonstrating the opposite effect as has already been seen with cAMP, and implying that the balance of cyclic nucleotides in the neural tube serves as yet another means of adapting the Shh response. |
