RRC ID 45697
著者 Budirahardja Y, Doan TD, Zaidel-Bar R.
タイトル Glycosyl phosphatidylinositol anchor biosynthesis is essential for maintaining epithelial integrity during Caenorhabditis elegans embryogenesis.
ジャーナル PLoS Genet
Abstract Glycosylphosphatidylinositol (GPI) is a post-translational modification resulting in the attachment of modified proteins to the outer leaflet of the plasma membrane. Tissue culture experiments have shown GPI-anchored proteins (GPI-APs) to be targeted to the apical membrane of epithelial cells. However, the in vivo importance of this targeting has not been investigated since null mutations in GPI biosynthesis enzymes in mice result in very early embryonic lethality. Missense mutations in the human GPI biosynthesis enzyme pigv are associated with a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease and renal anomalies. However, it is currently unknown how these phenotypes are linked to PIGV function. Here, we identify a temperature-sensitive hypomorphic allele of PIGV in Caenorhabditis elegans, pigv-1(qm34), enabling us to study the role of GPI-APs in development. At the restrictive temperature we found a 75% reduction in GPI-APs at the surface of embryonic cells. Consequently, ~80% of pigv-1(qm34) embryos arrested development during the elongation phase of morphogenesis, exhibiting internal cysts and/or surface ruptures. Closer examination of the defects revealed them all to be the result of breaches in epithelial tissues: cysts formed in the intestine and excretory canal, and ruptures occurred through epidermal cells, suggesting weakening of the epithelial membrane or membrane-cortex connection. Knockdown of piga-1, another GPI biosynthesis enzymes resulted in similar phenotypes. Importantly, fortifying the link between the apical membrane and actin cortex by overexpression of the ezrin/radixin/moesin ortholog ERM-1, significantly rescued cyst formation and ruptures in the pigv-1(qm34) mutant. In conclusion, we discovered GPI-APs play a critical role in maintaining the integrity of the epithelial tissues, allowing them to withstand the pressure and stresses of morphogenesis. Our findings may help to explain some of the phenotypes observed in human syndromes associated with pigv mutations.
巻・号 11(3)
ページ e1005082
公開日 2015-3-1
DOI 10.1371/journal.pgen.1005082
PII PGENETICS-D-14-03351
PMID 25807459
PMC PMC4373761
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans Proteins / biosynthesis Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Cytoskeletal Proteins / biosynthesis Cytoskeletal Proteins / genetics* Cytoskeletal Proteins / metabolism Embryonic Development / genetics* Epithelial Cells / metabolism Gene Expression Regulation, Developmental Glycosylphosphatidylinositols / biosynthesis* Glycosylphosphatidylinositols / genetics Hirschsprung Disease / genetics* Hirschsprung Disease / metabolism Humans Mannosyltransferases / biosynthesis Mannosyltransferases / genetics* Mannosyltransferases / metabolism Mice Mutation Protein Processing, Post-Translational / genetics Temperature
IF 5.175
引用数 3
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm2939