Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation

Lang, Michael; Lapierre, Lynne A.; Frotscher, Michael; Goldenring, James R.; Knapik, Ela W.

doi:10.1038/ng1880

Cited by 167 publications

(197 citation statements)

References 30 publications

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“…Consistent with the human phenotype, the Sec23a mutant zebrafish (crusher) also exhibits abnormal cartilage development (23). However, knockdown of either Sec23 isoform in zebrafish induced a phenotype similar to crusher, suggesting that zebrafish SEC23B may also be involved in cartilage maturation (23).…”

Section: Discussionmentioning

confidence: 70%

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SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

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In eukaryotic cells, newly synthesized secretory proteins require COPII (coat protein complex II) to exit the endoplasmic reticulum (ER). COPII contains five core components: SAR1, SEC23, SEC24, SEC13, and SEC31. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase and also plays a role in cargo recognition. Missense mutations in the human COPII paralogues SEC23A and SEC23B result in craniolenticulosutural dysplasia and congenital dyserythropoietic anemia type II, respectively. We now report that mice completely deficient for SEC23B are born with no apparent anemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues. In SEC23B-deficient embryonic pancreas, defects occur in exocrine and endocrine tissues shortly after differentiation. Pancreatic acini are completely devoid of zymogen granules, and the ER is severely distended. Similar ultrastructural alterations are also observed in salivary glands, but not in liver. Accumulation of proteins in the ER lumen activates the proapoptotic pathway of the unfolded protein response, suggesting a central role for apoptosis in the degeneration of these tissues in SEC23B-deficient embryos. Although maintenance of the secretory pathway should be required by all cells, our findings reveal a surprising tissue-specific dependence on SEC23B for the ER exit of highly abundant cargo, with high levels of SEC23B expression observed in professional secretory tissues. The disparate phenotypes in mouse and human could result from residual SEC23B function associated with the hypomorphic mutations observed in humans, or alternatively, might be explained by a species-specific shift in function between the closely related SEC23 paralogues. mammalian embryo abnormalities | vesicular transport protein | genetics | secretory granules | pancreatitis I n eukaryotic cells, secreted proteins and proteins that are targeted to the plasma membrane and internal organelles are synthesized in the endoplasmic reticulum (ER) and sorted through the secretory pathway. This process has been extensively studied, particularly in budding yeast (1). Proteins destined to traffic from the ER to the Golgi are packaged into COPII (coat protein complex II)-coated vesicles (2-4). COPII is composed of at least five proteins, a small GTPase SAR1 and two cytosolic protein complexes, SEC23-SEC24 and SEC13-SEC31 (5). The GTP-bound form of SAR1 binds to the ER membrane and recruits the SEC23-SEC24 heterodimer to form the "prebudding complex," which in turn recruits the outer coat composed of SEC13-SEC31 heterotetramers to complete the COPII coat structure (6).The COPII complex captures cargo into vesicles and mediates vesicle budding from the ER. Cargo recognition appears to be mediated primarily by the SEC24 subunit, which recognizes divergent export signals located in the cytosolic domain of cargo proteins (7,8). SEC23 and SAR1 also play a role in the recognition of at least a subset of cargos (9, 10). SEC23 is a GTPaseactivating protein (GAP) that activates the SAR1...

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Section: Discussionmentioning

confidence: 70%

“…1G). Mutations in SEC23A result in abnormalities of cartilage and bone development in humans and zebrafish (18,23). Although E18.5 Sec23b gt/gt neonates are smaller than WT controls, no skeletal abnormalities were evident by Alcian blue/alizarin red staining (Fig.…”

Section: Sec23b Deficiencymentioning

confidence: 99%

SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

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“…The rest of the phenotypes observed by the lack of Vmp1 might perfectly fit in the context of a secretory pathway defect including the apparent instability of the plasma membrane as described previously in other reports. 20,21 The autophagy defect in the Dictyostelium vmp1 mutant can also be seen in this context. We observe the accumulation of aberrant double-membrane structures in the mutant that is consistent with abnormal autophagic vesicles.…”

Section: Vmp1 In Dictyosteliummentioning

confidence: 97%

Vacuole membrane protein 1, autophagy and much more

Calvo‐Garrido¹,

Carilla-Latorre²,

Escalante³

2008

Autophagy

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“…An example is SEC23A (Saccharomyces cerevisiae; Sec23a), known to be required for normal collagen production and secretion (Townley et al 2008) and important for craniofacial development (Lang et al 2006). Transillumination of the chest wall in the LacZstained Sec23a mutant revealed a pattern of muscle, vasculature, and cartilage staining (Fig.…”

Section: Connective Tissue and Cartilagementioning

confidence: 99%

A lacZ reporter gene expression atlas for 313 adult KOMP mutant mouse lines

et al. 2015

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Expression of the bacterial beta-galactosidase reporter gene (lacZ) in the vector used for the Knockout Mouse Project (KOMP) is driven by the endogenous promoter of the target gene. In tissues from KOMP mice, histochemical staining for LacZ enzyme activity can be used to determine gene expression patterns. With this technique, we have produced a comprehensive resource of gene expression using both whole mount (WM) and frozen section (FS) LacZ staining in 313 unique KOMP mutant mouse lines. Of these, ∼80% of mutants showed specific staining in one or more tissues, while ∼20% showed no specific staining, ∼13% had staining in only one tissue, and ∼25% had staining in >6 tissues. The highest frequency of specific staining occurred in the brain (∼50%), male gonads (42%), and kidney (39%). The WM method was useful for rapidly identifying whole organ and some substructure staining, while the FS method often revealed substructure and cellular staining specificity. Both staining methods had >90% repeatability in biological replicates. Nonspecific LacZ staining occurs in some tissues due to the presence of bacteria or endogenous enzyme activity. However, this can be effectively distinguished from reporter gene activity by the combination of the WM and FS methods. After careful annotation, LacZ staining patterns in a high percentage of mutants revealed a unique structure-function not previously reported for many of these genes. The validation of methods for LacZ staining, annotation, and expression analysis reported here provides unique insights into the function of genes for which little is currently known.[Supplemental material is available for this article.]

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Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation

Cited by 167 publications

References 30 publications

SEC23B is required for the maintenance of murine professional secretory tissues

SEC23B is required for the maintenance of murine professional secretory tissues

Vacuole membrane protein 1, autophagy and much more

A lacZ reporter gene expression atlas for 313 adult KOMP mutant mouse lines

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