Defining the relationship of ciliary Arl13b and Smoothened

点击翻译按钮获取中文摘要

PROJECT SUMMARY Mutations to the Hedgehog signaling pathway are known to cause common birth defects. Here, I propose studying how the components of the Hedgehog pathway are regulated by the proteins of the primary cilium. We hope that by studying where these pathways intersect we can better understand how the two processes interact together in the healthy and disease states. The Hedgehog signaling pathway is known to influence a variety of aspects of early development, including the brain, spinal cord, and skeleton of the face, limbs and hands. Strangely, this pathway relies on a poorly understood cellular organelle called the primary cilium. I propose that the key to better understanding pathway function is my studying how the pathway’s components are regulated by the primary cilium and its ciliary proteins. I have hypothesized that a ciliary protein Arl13b is necessary for the full activation of Smoothened, the activator of the Hedgehog signaling cascade. The specific aims of this project are 1) to use a newly invented assay to measure Smoothened activation in the context of ciliary and non-ciliary Arl13b and 2) to characterize the physiological impact ciliary and non-ciliary Arl13b has on Smoothened activation in the developing mouse embryo. Through these methods, I aim to define the role of Arl13b in Smoothened activation and strive to better understand the link between the Hedgehog pathway and the primary cilium.