Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella

By G. Pazour, B. L. Dickert, Yvonne Vucica, E. S. Seeley, Joel L. Rosenbaum, G. Witman, Douglas G. Cole. Journal of Cell Biology, 2000

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Intraflagellar transport (IFT) is a rapid movement of multi-subunit protein particles along flagellar microtubules and is required for assembly and maintenance of eukaryotic flagella. We cloned and sequenced a Chlamydomonas cDNA encoding the IFT88 subunit of the IFT particle and identified a Chlamydomonas insertional mutant that is missing this gene. The phenotype of this mutant is normal except for the complete absence of flagella. IFT88 is homologous to mouse and human genes called Tg737. Mice with defects in Tg737 die shortly after birth from polycystic kidney disease. We show that the primary cilia in the kidney of Tg737 mutant mice are shorter than normal. This indicates that IFT is important for primary cilia assembly in mammals. It is likely that primary cilia have an important function in the kidney and that defects in their assembly can lead to polycystic kidney disease.

Subfields: Genetics, Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/45c4193b4026093d27d0f0d9ff44a2f719385fde

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Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer's vesicle is required for normal organogenesis (2005, background): “A role for cilia in this disorder is implied from the variety of cilia-associated proteins that, when mutated, can cause tubules to become cystic (Barr et al., 2001; Blacque et al., 2004; Fan et al., 2004; Kim et al., 2004; Morgan et al., 2002; Murcia et al., 2000; Mykytyn et al., 2004; Otto et al.,”
Determination of left–right patterning of the mouse embryo by artificial nodal flow (2002, background): “The lack of this nodal flow as a result of impaired ciliary development leads to randomization of body situ”
Integrative modeling reveals the molecular architecture of the intraflagellar transport A (IFT-A) complex (2022, background): “For example, IFT is critical for primary cilia assembly in mice, where assembly defects are linked to renal disorders, such as polycystic kidney disease (21), and IFT-dependent defects in Hedgehog signal transduction produce neural tube and skeletal abnormalities (22,23).”
Insights into Ciliary Genes and Evolution from Multi-Level Phylogenetic Profiling (2017, background): “diseases (Pazour et al. 2000), its functional roles have been deeply investigated and it is now considered as an essential extracellular sensor allowing integration of chemical, osmotic, mechanical or optical signals (Berbari et al.”
The Primary Cilium as a Complex Signaling Center (2009, background): “The discovery that perturbation of primary cilia function in the ift88 mouse (hereafter called ORPK) caused cyst formation in the kidney was a seminal finding that revealed the cilium as a clinically relevant organelle [15,16].”
Centrioles, centrosomes, and cilia in health and disease. (2009, background): “The cloning of one of the genes required for IFT in Chlamydomonas revealed that it was related to a gene that caused polycystic kidney disease when mutated in mice (Pazour et al., 2000).”
Gli2 and Gli3 Localize to Cilia and Require the Intraflagellar Transport Protein Polaris for Processing and Function (2005, background): “Polaris, the protein encoded by Tg737, is a core component of the mammalian IFT machinery and is required for the formation of all cilia and flagella [2,3].”
Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. (2004, background): “…and function, we undertook a comparative tubules underlies polycystic kidney disease, although genomics approach that subtracted the nonflagellated the exact process of cyst formation is not understood proteome of Arabidopsis from the shared proteome (Haycraft et al., 2001; Pazour et al., 2000).”
The ciliopathies: an emerging class of human genetic disorders. (2006, background): “elegans orthologs of Tg737, IFT88, and osm-5, respectively, encode intraflagellar transport proteins whose disruption leads to defective flagella in both species (37, 105).”
HEF1-dependent Aurora A activation induces disassembly of the primary cilium. (2007, positive): “In contrast to depletion of HEF1 or AurA, depletion of representative IFT proteins IFT88 (Figures 6A-C) and IFT20 (Supplemental Figure S6) limits the initial formation of cilia in hTERT-RPE1 cells similar to reports in other cell types (Follit et al., 2006; Pazour et al., 2000).”