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One or more keywords matched the following properties of Witman, George

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 The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly.
Academic Article LC2, the chlamydomonas homologue of the t complex-encoded protein Tctex2, is essential for outer dynein arm assembly.
Academic Article The unique catalytic subunit of sperm cAMP-dependent protein kinase is the product of an alternative Calpha mRNA expressed specifically in spermatogenic cells.
Academic Article Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella.
Academic Article Forward and reverse genetic analysis of microtubule motors in Chlamydomonas.
Academic Article Functional interaction between Chlamydomonas outer arm dynein subunits: the gamma subunit suppresses the ATPase activity of the alpha beta dimer.
Academic Article The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance.
Academic Article The vertebrate primary cilium is a sensory organelle.
Academic Article Oda5p, a novel axonemal protein required for assembly of the outer dynein arm and an associated adenylate kinase.
Academic Article A dynein light intermediate chain, D1bLIC, is required for retrograde intraflagellar transport.
Academic Article Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly.
Academic Article Novel role for a sterol response element binding protein in directing spermatogenic cell-specific gene expression.
Academic Article An insertional mutant of Chlamydomonas reinhardtii with defective microtubule positioning.
Academic Article Differential light chain assembly influences outer arm dynein motor function.
Academic Article HA-tagging of putative flagellar proteins in Chlamydomonas reinhardtii identifies a novel protein of intraflagellar transport complex B.
Academic Article A two-step procedure for efficient electrotransfer of both high-molecular-weight (greater than 400,000) and low-molecular-weight (less than 20,000) proteins.
Academic Article The outer dynein arm-docking complex: composition and characterization of a subunit (oda1) necessary for outer arm assembly.
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 DC3, the smallest subunit of the Chlamydomonas flagellar outer dynein arm-docking complex, is a redox-sensitive calcium-binding protein.
Academic Article Chlamydomonas flagella. I. Isolation and electrophoretic analysis of microtubules, matrix, membranes, and mastigonemes.
Academic Article DC3, the 21-kDa subunit of the outer dynein arm-docking complex (ODA-DC), is a novel EF-hand protein important for assembly of both the outer arm and the ODA-DC.
Academic Article Cell motility: deaf Drosophila keep the beat.
Academic Article Chlamydomonas flagella. II. The distribution of tubulins 1 and 2 in the outer doublet microtubules.
Academic Article Proteomic analysis of a eukaryotic cilium.
Academic Article Radial spoke proteins of Chlamydomonas flagella.
Academic Article Chlamydomonas reinhardtii hydin is a central pair protein required for flagellar motility.
Academic Article Functional analysis of an individual IFT protein: IFT46 is required for transport of outer dynein arms into flagella.
Academic Article The Chlamydomonas genome reveals the evolution of key animal and plant functions.
Academic Article Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella.
Academic Article Mutations in Hydin impair ciliary motility in mice.
Academic Article IC97 is a novel intermediate chain of I1 dynein that interacts with tubulin and regulates interdoublet sliding.
Academic Article The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella.
Academic Article Total internal reflection fluorescence (TIRF) microscopy of Chlamydomonas flagella.
Academic Article CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content.
Academic Article Regulation of flagellar motility by the conserved flagellar protein CG34110/Ccdc135/FAP50.
Academic Article Avalanche-like behavior in ciliary import.
Academic Article Chlamydomonas flagellar mutants lacking radial spokes and central tubules. Structure, composition, and function of specific axonemal components.
Academic Article Comparison of the microtubule proteins of neuroblastoma cells, brain, and Chlamydomonas flagella.
Academic Article Purification of calmodulin from Chlamydomonas: calmodulin occurs in cell bodies and flagella.
Academic Article Role of calmodulin in the flagellar axoneme: effect of phenothiazines on reactivated axonemes of Chlamydomonas.
Academic Article Synthesis, transport, and utilization of specific flagellar proteins during flagellar regeneration in Chlamydomonas.
Academic Article Detection of flagellar protein kinases on polyvinylidene difluoride membranes following sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
Academic Article Reactivation of Chlamydomonas cell models.
Academic Article The 78,000 M(r) intermediate chain of Chlamydomonas outer arm dynein isa WD-repeat protein required for arm assembly.
Academic Article ptx1, a nonphototactic mutant of Chlamydomonas, lacks control of flagellar dominance.
Concept Membrane Proteins
Concept DNA-Binding Proteins
Concept Algal Proteins
Concept HSP40 Heat-Shock Proteins
Concept Carrier Proteins
Concept Cell Cycle Proteins
Concept Luminescent Proteins
Concept Nuclear Proteins
Concept Recombinant Proteins
Concept Intracellular Signaling Peptides and Proteins
Concept Monomeric GTP-Binding Proteins
Concept Proteins
Concept Microtubule-Associated Proteins
Concept Membrane Transport Proteins
Concept Cytoskeletal Proteins
Concept Adaptor Proteins, Signal Transducing
Concept Green Fluorescent Proteins
Concept Recombinant Fusion Proteins
Concept Calcium-Binding Proteins
Concept Plant Proteins
Concept Fungal Proteins
Concept Neoplasm Proteins
Concept Drosophila Proteins
Concept Microfilament Proteins
Concept Microtubule Proteins
Concept Molecular Motor Proteins
Concept Protozoan Proteins
Concept Nerve Tissue Proteins
Concept Tumor Suppressor Proteins
Academic Article Characterization of THB1, a Chlamydomonas reinhardtii truncated hemoglobin: linkage to nitrogen metabolism and identification of lysine as the distal heme ligand.
Academic Article NPHP4 controls ciliary trafficking of membrane proteins and large soluble proteins at the transition zone.
Academic Article Flipping a phosphate switch on kinesin-II to turn IFT around.
Academic Article In situ localization of N and C termini of subunits of the flagellar nexin-dynein regulatory complex (N-DRC) using SNAP tag and cryo-electron tomography.
Academic Article TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport.
Academic Article Assembly of IFT trains at the ciliary base depends on IFT74.
Academic Article Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies.
Academic Article DRC3 connects the N-DRC to dynein g to regulate flagellar waveform.
Academic Article CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice.
Academic Article Superresolution Pattern Recognition Reveals the Architectural Map of the Ciliary Transition Zone.
Academic Article Intraflagellar transport is essential for mammalian spermiogenesis but is absent in mature sperm.
Academic Article Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin.
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.
Academic Article Proteome of the central apparatus of a ciliary axoneme.
Academic Article Chlamydomonas FAP70 is a component of the previously uncharacterized ciliary central apparatus projection C2a.
Concept Lipid-Linked Proteins
Concept Chloroplast Proteins
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