Systems Biology of the Mammalian Cilium
The primary cilium is a small, immotile, antenna-like structure that
emanates from the surface of virtually every cell in the
mammalian body and functions as a sensory organelle. Recent studies
revealed that the primary cilium receives both mechanical and
biochemical signals from other cells and the environment, and transmits
these signals to the nucleus to elicit a cellular response.
The proteins necessary for assembling the cilium, for transporting
receptors and channels to the cilium membrane, and for conveying
sensory information from the cilium back to the cell body are moved
bi-directionally within the cilium in a process called intraflagellar
transport (IFT).
Mutations in primary cilia genes cause a variety of different
human genetic diseases, in part because primary cilia are required
for the normal function of the sonic hedgehog (Shh),
Wingless-Int (Wnt),
and Platelet-derived growth factor receptor alpha (Pdgfra)
signaling pathways, which are important for the development and homeostasis
of many organ systems, including the skin and hair follicle. Comparative
genomics and proteomics studies have revealed that the cilia proteome has been highly
conserved throughout the evolution of eukaryotes and consists of approximately
300-500 proteins. However, the biological functions of the majority of these
proteins remain to be discovered. We are initiating a systems-biological approach
to understanding cilia assembly and function. For putative cilia genes that
have not yet been localized to cilia in model organisms, we are performing
translational GFP assays in transgenic worms (C. elegans). For cilia genes
that have already been localized to cilia in model organisms, we are generating
mutations in orthologous mouse cilia genes utilizing gene-driven ENU-induced
mutagenesis, conditional gene targeting, and gene traps.
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