Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival
Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival
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DOI：
10.7554/elife.45248
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发表时间：
2019-06-24
期刊：
影响因子：
7.7
通讯作者：
Stottmann, Rolf W.
中科院分区：
文献类型：
--
作者：
Lukacs, Marshall;Roberts, Tia;Stottmann, Rolf W.
糖基磷脂酰肌醇（GPI）锚将近150种蛋白质附着在细胞膜上。具有GPI生物合成基因致病性变体的患者通过未知的机制发展多种表型，包括癫痫发作、畸形面部特征和腭裂。我们发现了一种新的小鼠突变体（唇腭裂、水肿和露脑畸形; Clpex），其在GPI生物合成途径的组成部分-糖磷酸肌醇后附着蛋白2（Pgap 2）中具有亚形态突变。Clpex突变降低表面GPI表达。令人惊讶的是，Pgap 2显示出组织特异性表达，在大脑和面部富集。我们发现Clpex表型是由于神经嵴细胞（NCC）和颅神经上皮细胞的凋亡。我们发现在子宫内补充亚叶酸可以部分挽救唇裂表型。最后，我们产生了一种新的NCC特异性总GPI缺陷的小鼠模型。这些突变体发展中唇腭裂证明了以前没有记录的细胞自主作用GPI生物合成NCC发展。
Glycosylphosphatidylinositol (GPI) anchors attach nearly 150 proteins to the cell membrane. Patients with pathogenic variants in GPI biosynthesis genes develop diverse phenotypes including seizures, dysmorphic facial features and cleft palate through an unknown mechanism. We identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypo-morphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2), a component of the GPI biosynthesis pathway. The Clpex mutation decreases surface GPI expression. Surprisingly, Pgap2 showed tissue-specific expression with enrichment in the brain and face. We found the Clpex phenotype is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium. We showed folinic acid supplementation in utero can partially rescue the cleft lip phenotype. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency. These mutants developed median cleft lip and palate demonstrating a previously undocumented cell autonomous role for GPI biosynthesis in NCC development.