Tian E, Ten Hagen Kelly G
Developmental Glycobiology Unit, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4370, USA.
J Biol Chem. 2007 Jan 5;282(1):606-14. doi: 10.1074/jbc.M606268200. Epub 2006 Nov 10.
Epithelial tubes are essential for the proper function of a diverse array of eukaryotic organs. Here we present a novel class of genes required for maintaining epithelial cell shape, polarity, and paracellular barrier function in the Drosophila embryonic tracheal system. Mutations in one member of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family (pgant35A) are recessive lethal and result in tracheal tubes that are irregular in diameter and morphology. Further analysis of the pgant35A mutants reveals diminished levels of the apical determinant Crbs and the luminal marker 2A12, concomitant with increased staining in cytoplasmic vesicles within tracheal cells. GalNAc-containing glycoproteins are severely diminished along the apical region of the tracheal system as well. Tracheal cells become irregular in size and shape, and septate junction proteins are mislocalized to a more apical position. Most notably, paracellular barrier function is lost in the tracheal system of the mutants. Overexpression of wild type pgant35A under control of the trachea-specific breathless (btl) promoter results in partial rescue of the lethality. We propose a model where pgant35A is required to establish proper apical composition of tracheal cells by influencing apical delivery of proteins/glycoproteins. Disruption of the normal apical content results in altered cell morphology and loss of paracellular barrier function. These studies demonstrate a previously unrecognized requirement for mucin-type O-glycosylation in epithelial tube integrity and have obvious implications for epithelial morphogenesis in higher eukaryotes, since a unique ortholog to pgant35A exists in mammals.
上皮管对于多种真核生物器官的正常功能至关重要。在此，我们展示了一类新的基因，它们是果蝇胚胎气管系统中维持上皮细胞形状、极性和细胞旁屏障功能所必需的。UDP-GalNAc：多肽N-乙酰半乳糖胺基转移酶家族（pgant35A）的一个成员发生突变会导致隐性致死，并产生直径和形态不规则的气管管。对pgant35A突变体的进一步分析显示，顶端决定因子Crbs和管腔标记物2A12的水平降低，同时气管细胞内的细胞质囊泡染色增加。含有GalNAc的糖蛋白在气管系统的顶端区域也严重减少。气管细胞的大小和形状变得不规则，隔膜连接蛋白定位错误到更顶端的位置。最值得注意的是，突变体的气管系统中细胞旁屏障功能丧失。在气管特异性呼吸（btl）启动子的控制下过表达野生型pgant35A可部分挽救致死性。我们提出了一个模型，其中pgant35A通过影响蛋白质/糖蛋白的顶端递送，来建立气管细胞适当的顶端组成。正常顶端成分的破坏导致细胞形态改变和细胞旁屏障功能丧失。这些研究表明，黏蛋白型O-糖基化在上皮管完整性方面有此前未被认识到的需求，并且对高等真核生物的上皮形态发生有明显影响，因为在哺乳动物中存在pgant35A的独特直系同源物。
