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Search Results to George B Witman PhD

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Cilia and Flagella, Molecular Motors, Sensory Transduction, Proteomics, Molecular Basis for Diseases Involving Cilia and Flagella

Our research is concerned with the biology of cilia and flagella, including the non-motile primary cilia that are present on most cells in our bodies and function as cell antennae, receiving signals from the environment and transmitting these to the cell body. Our findings have important implications for human development and male infertility, and for diseases of the lung, kidney, and eye, all of which contain cilia. Such diseases are known as "ciliopathies."

In many of these studies we are using the unicellular Chlamydomonas, a model flagellated organism amenable to biochemical, genetic, and molecular genetic approaches. We recently completed a proteomic analysis of the Chlamydomonas flagellum. This has resulted in a virtual "gold mine" of data that has and will continue to form the basis for many exciting projects. Because the proteins of cilia and flagella have been highly conserved throughout evolution, the human homologues of most of these proteins are readily identified. This opens the door to understanding the functions of many previously uncharacterized ciliary proteins. We currently are investigating the functions of several proteins whose homologues in humans or mice are known to cause disease, including blindness (Leber congenital amaurosis), cystic kidney disease, hydrocephalus, and syndromic ciliopathies such as Bardet-Biedl syndrome and primary ciliary dyskinesia. Typically, we explore the functions of these proteins in Chlamydomonas and then in the mouse to be sure that what we learn from Chlamydomonas is applicable to mammals.

In addition, many members of this laboratory are participating in a large-scale project to generate and identify insertional Chlamydomonas mutants for all the genes encoding flagellar proteins. Chlamydomonas cells are transformed with a selectable marker that integrates at random into the genome, disrupting any gene at the site of insertion. Using PCR, we can then readily determine the genomic sequence flanking the insert, and thus identify the mutated gene. The mutant can then be characterized structurally and biochemically to understand the function of the mutated gene.

Finally, we are studying a process called "intraflagellar transport" (IFT), which involves the active movement of multi-subunit protein particles from the base to the tip of the cilium or flagellum, and back to the base again (Fig. 1). These particles carry cargo necessary for assembly and maintenance of the cilium or flagellum, and also transport signals from the cilium or flagellum to the cell body and vice versa (Fig. 2). We are characterizing the motors responsible for this transport, the individual polypeptides that make up the IFT particles, and the proteins and protein complexes that interact with the IFT particle and generally function as cargo adaptors. These studies are providing new insights into a process that is essential for the assembly of almost all cilia and flagella.

Witman Figure 1 a

Figure 1. The intraflagellar transport (IFT) machinery. During IFT, linear arrays of IFT particles (yellow) are transported towards the 'plus' (distal) ends of the flagellar outer doublet microtubules (blue) by kinesin-II (pink), and towards the 'minus' (proximal) ends of the microtubules by cytoplasmic dynein 1b (green). The IFT particles, which are composed of at least 19 different proteins, are believed to be carrying precursors that are necessary for the assembly of the flagellar axoneme. The IFT particles are linked to the flagellar membrane (grey lines), and there is evidence that their cargo also includes membrane proteins.

Witman Figure 2

Figure 2. IFT and targeting of proteins to the flagellar compartment. Flagellar membrane proteins are carried by vesicles from the Golgi apparatus to the base of the flagellum, where they fuse with the plasma membrane of the cell. In this figure, proteins destined for the flagellar membrane are sorted into specific vesicles that are then targeted to the base of the flagellum. This sorting and targeting appears to be aided by one or more IFT-particle proteins that cycle from the base of the flagellum back through the endomembrane system, where they become associated with the proteins that are destined for the flagellar membrane. Once the vesicle is exocytosed, the IFT-particle proteins, with attached flagellar membrane proteins, become incorporated into IFT particles and are moved through the flagellar pore (involving outer doublet-membrane links in the flagellar transition zone) into the flagellar compartment.


One or more keywords matched the following items that are connected to Witman, George

Item TypeName
Academic Article Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella.
Academic Article The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance.
Academic Article Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease.
Academic Article Intraflagellar transport.
Academic Article The vertebrate primary cilium is a sensory organelle.
Academic Article The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area.
Academic Article Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly.
Academic Article Axonemal dyneins.
Academic Article Identification of predicted human outer dynein arm genes: candidates for primary ciliary dyskinesia genes.
Academic Article A FAP46 mutant provides new insights into the function and assembly of the C1d complex of the ciliary central apparatus.
Academic Article Cycling of the signaling protein phospholipase D through cilia requires the BBSome only for the export phase.
Academic Article Cell motility: deaf Drosophila keep the beat.
Academic Article Proteomic analysis of a eukaryotic cilium.
Academic Article Mutations in Hydin impair ciliary motility in mice.
Academic Article High-speed digital imaging of ependymal cilia in the murine brain.
Academic Article CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content.
Academic Article A unified taxonomy for ciliary dyneins.
Academic Article Avalanche-like behavior in ciliary import.
Academic Article Interspecies conservation of outer arm dynein intermediate chain sequences defines two intermediate chain subclasses.
Concept Cilia
Academic Article Flagellar central pair assembly in Chlamydomonas reinhardtii.
Academic Article NPHP4 controls ciliary trafficking of membrane proteins and large soluble proteins at the transition zone.
Academic Article Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies.
Academic Article Reduced tubulin polyglutamylation suppresses flagellar shortness in Chlamydomonas.
Academic Article CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice.
Academic Article Intraflagellar transport is essential for mammalian spermiogenesis but is absent in mature sperm.
Academic Article Cilia and Diseases.
Academic Article IFT trains in different stages of assembly queue at the ciliary base for consecutive release into the cilium.
Academic Article The N-terminus of IFT46 mediates intraflagellar transport of outer arm dynein and its cargo-adaptor ODA16.
Academic Article A global analysis of IFT-A function reveals specialization for transport of membrane-associated proteins into cilia.

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