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The COPII cargo adapter SEC24C is essential for neuronal homeostasis
Bo Wang, … , David Ginsburg, Mondira Kundu
Bo Wang, … , David Ginsburg, Mondira Kundu
Published June 25, 2018
Citation Information: J Clin Invest. 2018;128(8):3319-3332. https://doi.org/10.1172/JCI98194.
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Research Article Development Neuroscience

The COPII cargo adapter SEC24C is essential for neuronal homeostasis

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Abstract

SEC24 family members are components of the coat protein complex II (COPII) machinery that interact directly with cargo or with other adapters to ensure proper sorting of secretory cargo into COPII vesicles. SEC24C is 1 of 4 mammalian SEC24 paralogs (SEC24A–D), which segregate into 2 subfamilies on the basis of sequence homology (SEC24A/SEC24B and SEC24C/SEC24D). Here, we demonstrate that postmitotic neurons, unlike professional secretory cells in other tissues, are exquisitely sensitive to loss of SEC24C. Conditional KO of Sec24c in neural progenitors during embryogenesis caused perinatal mortality and microcephaly, with activation of the unfolded protein response and apoptotic cell death of postmitotic neurons in the murine cerebral cortex. The cell-autonomous function of SEC24C in postmitotic neurons was further highlighted by the loss of cell viability caused by disrupting Sec24c expression in forebrain neurons of mice postnatally and in differentiated neurons derived from human induced pluripotent stem cells. The neuronal cell death associated with Sec24c deficiency was rescued in knockin mice expressing Sec24d in place of Sec24c. These data suggest that SEC24C is a major cargo adapter for COPII-dependent transport in postmitotic neurons in developing and adult brains and that its functions overlap at least partially with those of SEC24D in mammals.

Authors

Bo Wang, Joung Hyuck Joo, Rebecca Mount, Brett J. W. Teubner, Alison Krenzer, Amber L. Ward, Viraj P. Ichhaporia, Elizabeth J. Adams, Rami Khoriaty, Samuel T. Peters, Shondra M. Pruett-Miller, Stanislav S. Zakharenko, David Ginsburg, Mondira Kundu

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Figure 7

Deletion of SEC24C leads to elevated cellular stress and the demise of mature neurons derived from hiPSCs.

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Deletion of SEC24C leads to elevated cellular stress and the demise of m...
(A) Immunoblot analysis of cell extracts from WT and SEC24C-KO hiPSCs (clones 1 and 2) at 0, 3, and 6 weeks of neuronal differentiation. (B) Representative images of TUJ1 immunostaining of WT and SEC24C-KO hiPSCs at 6 weeks of differentiation. Scale bar: 10 μm. (C) Percentage of TUJ1+ cells per total cells (DAPI+) (mean ± SEM) shows normal differentiation of the SEC24C-KO hiPSCs compared with WT clones 1 and 2. (D) mRNA levels of CHOP in WT and SEC24C-KO hiPSCs at 0, 3, and 6 weeks of differentiation were determined by real-time RT-PCR. Data are presented as the mean ± SEM. (E) Representative images of immunostaining show pronounced nuclear localization of CHOP in SEC24C-KO hiPSCs at 6 weeks of differentiation. Scale bar: 10 μm. (F) Quantification of nucleus minus cytoplasm CHOP intensity shows significant enrichment of nuclear CHOP in SEC24C-KO hiPSCs. (G) Representative nuclear staining with DAPI and (H) quantification indicate a significant increase in the percentage of cells with condensed nuclei (mean ± SEM) in SEC24C-KO hiPSCs. Scale bar: 10 μm. Data were collected from 3 independent experiments. ***P < 0.001, by 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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