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

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 8

SEC24D can replace SEC24C during development of the embryonic mouse brain.

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SEC24D can replace SEC24C during development of the embryonic mouse brai...
(A) Western blot of brain extract prepared from Sec24c+/+ (n = 1) and Sec24cc-d/c-d mice (n = 1) shows almost complete abolishment of SEC24C and elevated expression of SEC24D. (B and C) Representative photograph (B) and mean (± SEM) fixed brain weight (C) of control (n = 7) and Sec24cc-d/c-d (n = 5) mice at E16.5. Scale bar: 200 μm. (D) Average ratio (± SEM) of brain weight to body weight in Sec24cc-d/c-d mice (n = 5) compared with that of control mice (n = 7). (E and F) Representative images of cleaved caspase-3 staining (E) and mean number (± SEM) of cleaved caspase-3+ cells revealed no obvious cell death in the brains of Sec24cc-d/c-d mice. Brain sections from Sec24cNes-cKO mice at the same age were used as a positive control (n = 3 mice/genotype). Scale bar: 500 μm. (G and H) Representative images and the number of SOX2+, TBR2+, and TBR1+ cells (mean ± SEM) were normal in the Sec24cc-d/c-d mouse brain (n = 3) compared with control mice (n = 3). Scale bar: 50 μm. **P < 0.01 and ***P < 0.001, by Student’s t test.