cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development

Zhang, Feng; Wang, Yaqing; Wang, Tao; Yao, Li; Lam, Sin Man; Huang, Xiahe; Fan, Junwan; Wang, Qin; Liu, Liang; Jiang, Yisheng; Zhang, Hongsheng; Shi, Lei; Yu, Mei; Shui, Guanghou; Wang, Yingchun; Gao, Fei; Zhang, Xiaohui; Xu, Zhiheng

doi:10.1073/pnas.1804083115

Cited by 21 publications

(34 citation statements)

References 57 publications

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“…Meningioma expressed antigen 6 is highly expressed in the central nervous system (CNS), however, its functions in cellular component trafficking of neurons, brain development and animal behaviors are poorly understood. Utilizing conditional knockout mice of MEA6 driven by Nestin-Cre, Zhang et al (2018) recently show that MEA6 is important for brain development and function. The deletion of MEA6 in the brain leads to reduced brain size, early death of mice, and behavioral defects, including abnormal limb-clasping reflex and impaired motor performance in the rotarod test (Zhang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Utilizing conditional knockout mice of MEA6 driven by Nestin-Cre, Zhang et al (2018) recently show that MEA6 is important for brain development and function. The deletion of MEA6 in the brain leads to reduced brain size, early death of mice, and behavioral defects, including abnormal limb-clasping reflex and impaired motor performance in the rotarod test (Zhang et al, 2018). These phenotypes may be ascribed to the deficits in neural development, since the dendrite outgrowth and branching, spine formation and maintenance, and astrocytic activation are damaged in the cerebral cortex of Nestin-Cre;MEA6 F/F mice (Zhang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The deletion of MEA6 in the brain leads to reduced brain size, early death of mice, and behavioral defects, including abnormal limb-clasping reflex and impaired motor performance in the rotarod test (Zhang et al, 2018). These phenotypes may be ascribed to the deficits in neural development, since the dendrite outgrowth and branching, spine formation and maintenance, and astrocytic activation are damaged in the cerebral cortex of Nestin-Cre;MEA6 F/F mice (Zhang et al, 2018). Nevertheless, it is not yet answered how MEA6 affects the development of the cerebellum.…”

Section: Introductionmentioning

confidence: 99%

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MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking

Wang

Cai

et al. 2019

Front. Cell. Neurosci.

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Meningioma expressed antigen 6 (MEA6), also called cutaneous T cell lymphoma-associated antigen 5 (cTAGE5), was initially found in tumor tissues. MEA6 is located in endoplasmic reticulum (ER) exit sites and regulates the transport of collagen, very low density lipoprotein, and insulin. It is also reported that MEA6 might be related to Fahr’s syndrome, which comprises neurological, movement, and neuropsychiatric disorders. Here, we show that MEA6 is critical to cerebellar development and motor performance. Mice with conditional knockout of MEA6 (Nestin-Cre;MEA6 F/F ) display smaller sizes of body and brain compared to control animals, and survive maximal 28 days after birth. Immunohistochemical and behavioral studies demonstrate that these mutant mice have defects in cerebellar development and motor performance. In contrast, PC deletion of MEA6 (pCP2-Cre;MEA6 F/F ) causes milder phenotypes in cerebellar morphology and motor behaviors. While pCP2-Cre;MEA6 F/F mice have normal lobular formation and gait, they present the extensive self-crossing of PC dendrites and damaged motor learning. Interestingly, the expression of key molecules that participates in cerebellar development, including Slit2 and brain derived neurotrophic factor (BDNF), is significantly increased in ER, suggesting that MEA6 ablation impairs ER function and thus these proteins are arrested in ER. Our study provides insight into the roles of MEA6 in the brain and the pathogenesis of Fahr’s syndrome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking

Wang

Cai

et al. 2019

Front. Cell. Neurosci.

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“…TANGO1 can bind to ERGIC membrane and recruit it to ERES, providing additional membrane sources for ER microdomains [36]. Meanwhile, cTAGE5 promotes secretion of collagen by concentrating SEC12 at ERES; cTAGE5 also mediates the interaction between SAR1-GTP and SEC23 [37,38] and can enhance the GAP (GTP hydrolysis-activating protein) activity of SEC23 toward SAR1 [39]. Bulky cargoes such as collagen are also observed in ER-derived tubular carrier [40,41], although little is known about the molecular nature of the synthesis, transport, and fusion with target membranes of these tubular carriers.…”

Section: Vesicle Buddingmentioning

confidence: 99%

“…Fahr disease is a progressive neurological disorder with a highly variable clinical presentation encompassing neuropsychiatric symptoms, including psychosis, motor impairment, and mood disorders. The conditional knockout of cTAGE5 in murine brains leads to severe developmental defects and impaired dendrite outgrowth [38]. Additionally, inactivating TFG in mice is embryonic-lethal, and TFG point mutations have been identified in several patients with neurological diseases, including HSP, Charcot-Marie-Tooth disease, and hereditary motor and sensory neuropathy [86][87][88][89][90].…”

Section: Er-to-golgi Trafficking Defects and Neurological Disordersmentioning

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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Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients

Borges-Medeiros

Oliveira

2019

J Mol Neurosci

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cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development

Cited by 21 publications

References 57 publications

MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking

MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking

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

Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients

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