Murine SEC24D Can Substitute Functionally for SEC24C<i>in vivo</i>

Ej, Adams; Khoriaty, Rami; Kiseleva, Anya; Cleuren, A.C.A.; Tomberg, Kärt; Gergics, Péter; O’Shea, K. Sue; Saunders, Thomas L.; Ginsburg, David

doi:10.1101/284398

Cited by 2 publications

(5 citation statements)

References 44 publications

(47 reference statements)

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“…However, these mice failed to suckle and died shortly after birth. Although the brains of E16.5 Sec24c c-d/c-d mice showed minimal reductions in size and weight compared with those measures in littermate controls (Sec24c +/+ or Sec24c +/c-d ) (Figure 8, B and C), the ratio of brain weight to body weight in Sec24c c-d/c-d mice was marginally increased relative to that of littermate controls ( Figure 8D), because their overall body size and weight were reduced (34). Moreover, unlike the brains of E16.5 Sec24c Nes -cKO mice, the brains of Sec24c c-d/c-d mice showed no increase in cleaved caspase-3 staining compared with that in littermate controls (Figure 8, E and F).…”

Section: Methodsmentioning

confidence: 93%

“…To explore the extent of functional overlap between SEC24C and SEC24D in the brain, we used a recently developed knockin mouse model, in which Sec24c exons were replaced by corresponding sequences from Sec24d (Sec24c c-d ), resulting in a Sec24c-d fusion gene (34). Immunoblot analyses confirmed the loss of SEC24C expression and the increase in SEC24D expression in the brains of Sec24c c-d/c-d mice ( Figure 8A).…”

Section: Methodsmentioning

confidence: 95%

“…Sec24c fl/fl (stock 024867), Nes-Cre (stock 003771), Cam-k2a-Cre (stock 005359), and Chop -/-(stock 005530) mice were obtained from The Jackson Laboratory. Sec24 c-d mice were generated as described previously (34). Briefly, a targeting construct containing the coding sequence of SEC24D, spanning from Val41 to Asn1032, was microinjected into Sec24c GT embryonic stem cells (32) to replace exons 3-23 of SEC24C through dual recombinase-mediated cassette exchange.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we generated mice lacking Sec24c expression in the CNS to evaluate the function of SEC24C in neurons. We also tested the degree of functional overlap between SEC24C and SEC24D in neurons by using a recently developed murine model, in which Sec24d was knocked into the Sec24c locus (34).…”

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confidence: 99%

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The COPII cargo adapter SEC24C is essential for neuronal homeostasis

Wang¹,

Joo²,

Mount³

et al. 2018

Journal of Clinical Investigation

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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.

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Section: Methodsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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The COPII cargo adapter SEC24C is essential for neuronal homeostasis

Wang¹,

Joo²,

Mount³

et al. 2018

Journal of Clinical Investigation

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“…For example, SEC24A and SEC24B associate with LxxLE and DxE ER-exit motifs, and SEC24C and SEC24D have surface grooves to bind the IxM motif [9,10,13,22]. That one SEC24 isoform can substitute the function of another closely related isoform is suggested by the observation that SEC24C and SEC24D are essential for normal embryogenesis, but SEC24D expression under the Sec24c promoter rescues the embryonic lethality caused by Sec24c deficiency [23,24]. A similar observation has been made with the closely related SEC23A and SEC23B isoforms [25].…”

Section: Cargo Selectionmentioning

confidence: 99%

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

Wang

Stanford

Kundu

2020

Cells

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Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. OverviewApproximately one-third of all proteins encoded by the mammalian genome are exported from the endoplasmic reticulum (ER) and transported to the Golgi apparatus, where they are sorted for delivery to their final destination in membrane compartments or secretory vesicles [1]. Secretory proteins are co-translationally inserted into the ER and then packaged into transport vesicles at ER exit sites (ERES, also known as the transitional ER), which are specialized regions of smooth ER [1].The stepwise process for segregating and exporting cargo from the ER is similar in yeast, plant, and mammalian cells and relies on several essential proteins (SAR1-GTPase, SEC23, SEC24, SEC13, and SEC31). The first step involves the conversion of SAR1-GDP to SAR1-GTP by the guanine nucleotide exchange factor SEC12, which resides in the ER membrane [2,3]. This results in the localization of SAR1-GTP to the ER membrane, triggering the recruitment of SEC23/24 heterodimers [4]. The membrane localization of the SEC23/24 heterodimers promotes the entrapment of cargo by SEC24 and the recruitment of SEC13/31 heterotetramers. The sequential binding of SEC13/31 heterotetramers to SAR1-GTP-SEC23/24 complexes drives the formation of a cage-like lattice [4][5][6][7]. Although the basic steps involved in generating COPII vesicles are well understood and can be reconstituted in vitro, additional proteins are involved in regulating the process in cells. Differences between yeast and mammalian ER-to-Golgi trafficking include the presence of multiple COPII protein isoforms and an ER-Golgi intermediate compartment (ERGIC) in mammals, which likely evolved to help meet the cell-type-specific demands of multicellular organisms.Unlike other cell types, neurons consist of two compartments: the somatodendritic compartment and the axonal compartment. These compartments are separated by the axonal-exclusion zone located at the base of the axon, where proteins are either permitted into or excluded from the axon. Neurons are

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Murine SEC24D Can Substitute Functionally for SEC24Cin vivo

Cited by 2 publications

References 44 publications

The COPII cargo adapter SEC24C is essential for neuronal homeostasis

The COPII cargo adapter SEC24C is essential for neuronal homeostasis

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

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