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 5

Postnatal deletion of Sec24c in the forebrain leads to hyperactivity and altered anatomy in the forebrain.

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Postnatal deletion of Sec24c in the forebrain leads to hyperactivity and...
(A) Representative image of fixed brains dissected from a 12-month-old Sec24cCamk2a-cKO mouse and littermate control. Scale bar: 500 μm. (B and C) Brain (B) and body (C) weights (mean ± SEM) of 12-month-old Sec24cCamk2a-cKO and control mice (n = 4 mice/genotype). (D–F) Behavioral tests were performed using 2-month-old Sec24cCamk2a-cKO mice (n = 8) and age-matched controls (n = 17) and 12-month-old Sec24cCamk2a-cKO mice (n = 4) and age-matched controls (n = 5). Total distance traveled (mean ± SEM) (D) and distance traveled in the center (mean ± SEM) (E) by mice subjected to the open field test. (F) Mean time (± SEM) spent in the open arms during the indicated intervals by mice subjected to the elevated plus maze test. (G–I) Brain sections from 12-month-old Sec24cCamk2a-cKO and littermate control mice (n = 3 mice/genotype) were stained with Nissl and Luxol fast blue or immunostained with anti-NeuN antibody. Representative images (G), mean cortical thickness (± SEM) (H), and mean neuronal numbers (± SEM) (I) are shown. (G) Scale bars: 1 mm and 100 μm (insets). LFB, Luxol fast blue. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test.