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 characterized. By contrast, the 'PCP effector' proteins, such as Intu and Fuz, remain largely unstudied. 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.
Bibliographical noteFunding Information:
The ES cell clone for making the Fuz mutant mouse was provided by Lexicon Pharmaceuticals. We thank P. Paukstelis for aid with structural modelling, S. Vokes for critical comments on the manuscript, and Wei H. for technical help with histology and immunostaining. Phil Abitua is supported by a Diversity Supplement from the NIH/NIGMS. This work was supported by grants to K.J.L from the Wellcome Trust and the BBSRC; to E.M.M. from the NSF, NIH, Welch Foundation (F-1515), Texas Institute for Drug and Diagnostic Development, and a Packard Fellowship; grants to J.B.W. from the NIH/NIGMS, The March of Dimes, The Burroughs Wellcome Fund, the Sandler Program for Asthma Research, and the Texas Advanced Research Program; and by grants to R.H.F. from the NIH and The Texas A&M Institute for Genomic Medicine.
All Science Journal Classification (ASJC) codes
- Cell Biology