The planar cell polarity (PCP) effector Fuz had not been studied in mice. Due to disrupted ciliogenesis, Fuz mutant mice show neural tube and skeletal defects. Fuz regulates trafficking of membrane cargoes to cilia through its interaction with a GTPase of the Rab family. The planar cell polarity (PCP) signalling pathway is essential for embryonic development because it governs diverse cellular behaviours, and 'core PCP' proteins, such as Dishevelled and Frizzled, have been extensively characterized1,2,3,4. By contrast, the 'PCP effector' proteins, such as Intu and Fuz, remain largely unstudied5,6. These proteins are essential for PCP signalling, but they have never been investigated in mammals and their cell biological activities remain entirely unknown. We report here that Fuz mutant mice show neural tube defects, skeletal dysmorphologies and Hedgehog signalling defects stemming from disrupted ciliogenesis. Using bioinformatics and imaging of an in vivo mucociliary epithelium, we established a central role for Fuz in membrane trafficking, showing that Fuz is essential for trafficking of cargo to basal bodies and to the apical tips of cilia. Fuz is also essential for exocytosis in secretory cells. Finally, we identified a Rab-related small GTPase as a Fuz interaction partner that is also essential for ciliogenesis and secretion. These results are significant because they provide new insights into the mechanisms by which developmental regulatory systems such as PCP signalling interface with fundamental cellular systems such as the vesicle trafficking machinery.

Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been c...

3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor α (ERα) interactions. In this study, we used 3MC and 3,3′,4,4′,5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ERα but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ERα, and this was confirmed in a competitive ERα binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ERα/YFP-ERα interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ERα (but not AhR) association with the estrogen-responsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ERα-dependent transactivation and extend the number of ligands that activate both AhR and ERα. (Cancer Res 2006; 66(4): 2459-67)