Expanding EMC Foldopathies: Topogenesis Deficits Alter the Neural Crest

Abstract

The endoplasmic reticulum membrane protein complex (EMC) is essential for the insertion of a wide variety of transmembrane proteins into the plasma membrane across cell types. Each EMC is composed of Emc1-7, Emc10, and either Emc8 or Emc9. Recent human genetics studies have implicated variants in EMC genes as the basis for a group of human congenital diseases. The patient phenotypes are varied but appear to affect a subset of tissues more prominently than others. Namely, craniofacial development seems to be commonly affected. We previously developed an array of assays in Xenopus tropicalis to assess the effects of emc1 depletion on the neural crest, craniofacial cartilage, and neuromuscular function. We sought to extend this approach to additional EMC components identified in patients with congenital malformations. Through this approach we determine that EMC9 and EMC10 are important for neural crest development and the development of craniofacial structures. The phenotypes observed in patients and our Xenopus model were similar to EMC1 loss of function likely due to a similar mechanism of dysfunction in transmembrane protein topogenesis.

ER membrane complex (EMC): Structure, functions, and roles in diseases

“…Crucially, EMC1 performs the same function in the β‐catenin‐signaling pathway as EMC9 and 10. Deletion of EMC9 or EMC10 has been shown to result in NCC dysfunction by disrupting WNT signaling, leading to human disease 75 . Our research group has demonstrated an association between the deletion of EMC proteins and retinal degeneration, including EMC1, 3, and 6.…”

“…Deletion of EMC9 or EMC10 has been shown to result in NCC dysfunction by disrupting WNT signaling, leading to human disease. 75 Our research group has demonstrated an association between the deletion of EMC proteins and retinal degeneration, including EMC1, 3, and 6. Specifically, we found that Emc1-specific knockout (KO) in mouse retina reduces levels of membrane proteins and ER chaperones, suggesting that the loss of membrane proteins is a primary cause of photoreceptor degeneration.…”