Gray Ryan S, Abitua Philip B, Wlodarczyk Bogdan J, Szabo-Rogers Heather L, Blanchard Otis, Lee Insuk, Weiss Greg S, Liu Karen J, Marcotte Edward M, Wallingford John B, Finnell Richard H
Dept. of Molecular Cell and Developmental Biology, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, USA.
Nat Cell Biol. 2009 Oct;11(10):1225-32. doi: 10.1038/ncb1966. Epub 2009 Sep 20.
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.
平面细胞极性（PCP）信号通路对胚胎发育至关重要，因为它调控多种细胞行为，并且诸如Dishevelled和Frizzled等“核心PCP”蛋白已得到广泛研究。相比之下，诸如Intu和Fuz等“PCP效应器”蛋白在很大程度上仍未被研究。这些蛋白对PCP信号传导至关重要，但从未在哺乳动物中进行过研究，其细胞生物学活性也完全未知。我们在此报告，Fuz突变小鼠表现出神经管缺陷、骨骼畸形以及由于纤毛发生中断导致的刺猬信号通路缺陷。通过生物信息学和体内黏液纤毛上皮成像，我们确定了Fuz在膜转运中的核心作用，表明Fuz对于货物转运至基体和纤毛顶端至关重要。Fuz对分泌细胞的胞吐作用也必不可少。最后，我们鉴定出一种与Rab相关的小GTP酶作为Fuz相互作用伴侣，其对纤毛发生和分泌也至关重要。这些结果意义重大，因为它们为诸如PCP信号传导等发育调节系统与诸如囊泡转运机制等基本细胞系统相互作用的机制提供了新见解。
