Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development
Pu Wang, … , Scott E. Parnell, Yue Xiong
Pu Wang, … , Scott E. Parnell, Yue Xiong
Published July 25, 2019
Citation Information: J Clin Invest. 2019;129(10):4393-4407. https://doi.org/10.1172/JCI129107.
View: Text | PDF
Research Article Development Genetics

Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development

  • Text
  • PDF
Abstract

3-M primordial dwarfism is an inherited disease characterized by severe pre- and postnatal growth retardation and by mutually exclusive mutations in 3 genes, CUL7, OBSL1, and CCDC8. The mechanism underlying 3-M dwarfism is not clear. We showed here that CCDC8, derived from a retrotransposon Gag protein in placental mammals, exclusively localized on the plasma membrane and was phosphorylated by CK2 and GSK3. Phosphorylation of CCDC8 resulted in its binding first with OBSL1, and then CUL7, leading to the membrane assembly of the 3-M E3 ubiquitin ligase complex. We identified LL5β, a plasma membrane protein that regulates cell migration, as a substrate of 3-M ligase. Wnt inhibition of CCDC8 phosphorylation or patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β. Deletion of Ccdc8 in mice impaired trophoblast migration and placental development, resulting in intrauterine growth restriction and perinatal lethality. These results identified a mechanism regulating cell migration and placental development that underlies the development of 3-M dwarfism.

Authors

Pu Wang, Feng Yan, Zhijun Li, Yanbao Yu, Scott E. Parnell, Yue Xiong

×

Figure 1

Deletion of Ccdc8 causes perinatal lethality, intrauterine growth restriction, and placental defects.

Options: View larger image (or click on image) Download as PowerPoint
Deletion of Ccdc8 causes perinatal lethality, intrauterine growth restri...
(A) Genotypes of embryos and live offspring collected from Ccdc8+/– mouse intercrosses. (B) Gross appearance of Ccdc8+/+, Ccdc8+/–, and Ccdc8–/– embryos at E18.5. Scale bar: 1 cm. (C) Body weights of 41 E18.5 embryos collected from 4 Ccdc8+/– mouse intercrosses. Data are represented as mean ± SEM. Significance was determined by 1-way ANOVA and Bonferroni’s multiple-comparisons test. **Adjusted P < 0.01. (D) Quantification of the area of maternal and fetal blood vessels in the labyrinth. Data are represented as mean ± SEM from 5 randomly selected areas. Significance was determined by Student’s t test. ***P < 0.001. (E) H&E staining of E12.5 placentas with Ccdc8+/+ or Ccdc8–/– fetal genotype. Left: Gross staining pattern. Scale bars: 500 μm. Right: Boxed areas in the left panels were enlarged and maternal and fetal blood vessels are marked with red and blue, respectively. Scale bars: 20 μm. (F) Single-molecule RNA in situ hybridization of Ccdc8+/+ and Ccdc8–/– placenta. Yellow dashed line indicates the border between spongiotrophoblast layer (Sp) and labyrinth (Lab). Scale bars: 10 μm. (G) Ccdc8 mRNA expression pattern shown by RNA in situ hybridization (ISH) of a midsagittal section from an E12.5 embryo. H&E staining is from the adjacent section. Scale bars: 1 mm. NS indicates P ≥ 0.05.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts