Members of the Hedgehog (Hh) family of signaling proteins play critical roles in coordinating cell growth and differentiation. Many embryonic tissues and structures require Hh signaling for their formation during development and thus a large number of birth defects have been associated with reduced Shh signaling. One of the more striking malformations is holoprosencephaly that may result from reduced Sonic hedgehog (Shh) signaling by a variety of means including genetic mutations in Shh and other pathway components, teratogen exposure, or inborn errors of cholesterol biosynthesis. Hh proteins are secreted from a localized source and elicit distinct, concentration-dependent responses in a field of neighboring cells. A unique feature of Hh protein biogenesis is the production of a mature signaling domain that is covalently modified by cholesteryl and palmitoyl adducts. Given the importance of morphogen distribution, we are interested in the detailed roles of the lipid modifications on the spatial deployment of Shh in the developing neural tube. Towards this end, we have developed a visualizable Shh molecule to characterize the cellular mechanisms that package, propagate and receive a morphogen with unique biochemical properties. We also propose to generate lines of transgenic zebrafish with localized expression of photoactivatible Shh-GFP to measure the contribution of each adduct on the rate of Shh diffusion and degradation. ? ? ?
| Grover, Vandana K; Valadez, J Gerardo; Bowman, Aaron B et al. (2011) Lipid modifications of Sonic hedgehog ligand dictate cellular reception and signal response. PLoS One 6:e21353 |
| Rush, Sarah Z; Abel, Ty W; Valadez, Juan G et al. (2010) Activation of the Hedgehog pathway in pilocytic astrocytomas. Neuro Oncol 12:790-8 |
| Sarangi, A; Valadez, J G; Rush, S et al. (2009) Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival. Oncogene 28:3468-76 |
