Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis
Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis
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DOI：
10.1101/gad.13.11.1475
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发表时间：
1999-06-01
影响因子：
10.5
通讯作者：
Soriano, P
中科院分区：
文献类型：
--
作者：
Komada, M;Soriano, P
Hrs是与Vps 27 p同源的早期内体蛋白，Vps 27 p是囊泡运输所需的酵母蛋白。Hrs具有FYVE双锌指结构域，其特异性结合磷脂酰肌醇（3）-磷酸，并且在参与囊泡运输的几种蛋白质中是保守的。为了理解Hrs的生理作用，我们产生了携带该基因无效突变的小鼠。Hrs纯合子突变胚胎发育时，其腹侧区域位于卵黄囊外，有两个独立的双侧心管（心裂），缺乏前肠，并在胚胎第11天（E11）左右死亡。这些表型产生于腹侧折叠形态发生的缺陷，通常发生在E8.0左右。显着的细胞凋亡中检测到的突变体胚胎的腹侧区域内的定形内胚层，这表明一个重要的作用，这个胚层腹侧折叠形态发生。在包括定形内胚层在内的几种组织中的突变体中检测到异常扩大的早期内体，这表明通过早期内体的囊泡运输缺陷是突变体表型的基础。在用渥曼青霉素处理的细胞中，Hrs的囊泡定位被破坏，暗示Hrs在膜运输的磷脂酰肌醇3-激酶途径中。
Hrs is an early endosomal protein homologous to Vps27p, a yeast protein required for vesicular trafficking. Hrs has a FYVE double zinc finger domain, which specifically binds phosphatidylinositol(3)-phosphate and is conserved in several proteins involved in vesicular traffic. To understand the physiological role of Hrs, we generated mice carrying a null mutation of the gene. Hrs homozygous mutant embryos developed with their ventral region outside of the yolk sac, had two independent bilateral heart tubes (cardia bifida), lacked a foregut, and died around embryonic day 11 (E11). These phenotypes arise from a defect in ventral folding morphogenesis that occurs normally around E8.0. Significant apoptosis was detected in the ventral region of mutant embryos within the definitive endoderm, suggesting an important role of this germ layer in ventral folding morphogenesis. Abnormally enlarged early endosomes were detected in the mutants in several tissues including definitive endoderm, suggesting that a deficiency in vesicular transport via early endosomes underlies the mutant phenotype. The vesicular localization of Hrs was disrupted in cells treated with wortmannin, implicating Hrs in the phosphatidylinositol 3-kinase pathway of membrane trafficking.