Polaris, a Protein Involved in Left-Right Axis Patterning, Localizes to Basal Bodies and Cilia

Abstract

Mutations in Tg737 cause a wide spectrum of phenotypes, including random left-right axis specification, polycystic kidney disease, liver and pancreatic defects, hydrocephalus, and skeletal patterning abnormalities. To further assess the biological function of Tg737 and its role in the mutant pathology, we identified the cell population expressing Tg737 and determined the subcellular localization of its protein product called Polaris. Tg737 expression is associated with cells possessing either motile or immotile cilia and sperm. Similarly, Polaris concentrated just below the apical membrane in the region of the basal bodies and within the cilia or flagellar axoneme. The data suggest that Polaris functions in a ciliogenic pathway or in cilia maintenance, a role supported by the loss of cilia on the ependymal cell layer in ventricles of Tg737 orpk brains and by the lack of node cilia in Tg737 ⌬2-3␤Gal mutants.

Cilium-generated signaling and cilia-related disorders

“…69,60,70 Although nephrocystin 3 and nephrocystin 4 have not been localized to cilia, nephrocystin 4 forms a complex with nephrocystin, suggesting that they may be colocalized in cilia. 63 Disruption of several additional genes in mouse also leads to PKD, and the protein products of at least two, cystin 65,71 and polaris/Tg737, 65,[72][73][74] are localized to cilia.…”

Axonemal protofilament ribbons, DM10 domains, and the link to juvenile myoclonic epilepsy

“…Several studies have linked defects in ependymal ciliary motility with formation of hydrocephalus. For example, mutations in the Mdnah5 axonemal outer arm dynein heavy chain [Ibanez-Tallon et al, 2004], the sperm-associated antigen Spag6, which is related to the Chlamydomonas central pair microtubule complex protein PF16 [Smith and Lefebvre, 1996;Sapiro et al, 2002], and Polaris/Tg737 [Taulman et al, 2001], a component of the intraflagellar transport machinery [Pazour et al, 2000], all result in this phenotype; the dynein heavy chain mutant also exhibited stenosis of the cerebral aqueduct during the later stages of brain development [Ibanez-Tallon et al, 2004]. In addition, two rodent models for hydrocephalus (the WIC-Hyd rat and SUMS/ NP mouse) have ciliary defects although the mutated genes are not currently known [Bruni et al, 1988;Torikata et al, 1991].…”

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

“…31 Tg737 encodes the polaris (IFT88) protein whose function is required for cilia formation. 58 Tg737 orpk mutants are severely growth retarded and normally die within 2 weeks of birth, with very few surviving to 21 days of age (average age of death on the FVB background is approximately 5 days old). The cause of the early lethality in the Tg737 orpk mutants remains elusive, but it is likely due to a combination of pathologies in multiple tissues that include cystic lesions in the kidney, hydrocephalus, and hepatic and pancreatic abnormalities.…”

“…Both the kidney and brain pathologies have been associated with stunted or absent cilia. 58 Here we analyze the association between pancreatic pathology and cilia defects. Our findings with regards to the exocrine pancreatic defects are similar to that recently reported by Cano et al 59 The pathology includes cystic structures in the ducts, severe acinar cell apoptosis, acinar cell vacuolization with increased amylase release, abnormal intrapancreatic activation of carboxypeptidase, and elevated proliferation of the ductal epithelium associated with increased b-catenin expression.…”