Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival

• Published in: eLife Vol. 8
• Main Authors: Lukacs, Marshall, Roberts, Tia, Chatuverdi, Praneet, Stottmann, Rolf W
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 24.06.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Acids; Animal experimentation; Animals; Apoptosis; Biosynthesis; Cell membranes; Cell Survival; Cleft lip; Cleft lip/palate; Cleft palate; congenital disorders of glycosylation; craniofacial; Defects; development; Developmental Biology; Edema; Embryonic development; Ethanol; Exencephaly; Folic/folinic acid; Folinic acid; Gene mutation; Genetic research; Genomes; Genotype & phenotype; Glycerol; Glycosylphosphatidylinositol; Glycosylphosphatidylinositols; Glycosylphosphatidylinositols - biosynthesis; Heart - embryology; Liver; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mutagenesis; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Neural circuitry; Neural crest; Neural Crest - metabolism; Neural tube; Neural Tube - embryology; Novels; Observations; Phenotypes; Physiological aspects; Proteins; Seizures; Seizures (Medicine); Skull; Software; Statistical analysis; Supplements; United States; United States > US; mouse; development; developmental biology; neural crest; craniofacial; Folic/folinic acid; glycosylphosphatidylinositol; congenital disorders of glycosylation
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.45248

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 ( with a hypo-morphic mutation in , a component of the GPI biosynthesis pathway. The mutation decreases surface GPI expression. Surprisingly, showed tissue-specific expression with enrichment in the brain and face. We found the phenotype is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium. We showed folinic acid supplementation 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.