Disrupted ER membrane protein complex-mediated topogenesis drives congenital neural crest defects
Open Access
- 3 February 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (2), 813-826
- https://doi.org/10.1172/JCI129308
Abstract
Multipass membrane proteins have a myriad of functions, including transduction of cell-cell signals, ion transport, and photoreception. Insertion of these proteins into the membrane depends on the endoplasmic reticulum (ER) membrane protein complex (EMC). Recently, birth defects have been observed in patients with variants in the gene encoding a member of this complex, EMC1. Patient phenotypes include congenital heart disease, craniofacial malformations, and neurodevelopmental disease. However, a molecular connection between EMC1 and these birth defects is lacking. Using Xenopus, we identified defects in neural crest cells (NCCs) upon emc1-depletion. We then used unbiased proteomics and discovered a critical role for emc1 in WNT signaling. Consistent with this, readouts of WNT signaling and Frizzled (Fzd) levels were reduced in emc1-depleted embryos, while NCC defects could be rescued with beta-catenin. Interestingly, other transmembrane proteins were mislocalized upon emc1 depletion, providing insight into additional patient phenotypes. To translate our findings back to humans, we found that EMC1 was necessary for human NCC development in vitro. Finally, we tested patient variants in our Xenopus model and found the majority to be loss-of-function alleles. Our findings define molecular mechanisms whereby EMC1 dysfunction causes disease phenotypes through dysfunctional multipass membrane protein topogenesis.Funding Information
- National Institute of General Medical Sciences (T32GM07205)
- National Institute of General Medical Sciences (T32GM007223)
- National Institute of Dental and Craniofacial Research (F32DE027862)
- National Institute of Dental and Craniofacial Research (R01DE017914)
- Hartwell Foundation (Hartwell Individual Biomedical Research Award)
- National Institute of Child Health and Human Development (R01HD081379)
- Edward Mallinckrodt, Jr. Foundation (Mallinckrodt Scholar)
- Paul and Daisy Soros Fellowship for New Americans (N/A)
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