GM130 Regulates Golgi-Derived Spindle Assembly by Activating TPX2 and Capturing Microtubules

Wei, Jen Hsuan; Zhang, Zi Chao; Wynn, R. Max; Seemann, Joachim

doi:10.1016/j.cell.2015.06.014

Cited by 92 publications

(124 citation statements)

References 55 publications

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“…This patch lies within the putative nuclear localization signal (NLS) for MNB/DYRK1a (Becker et al, 1998), which could serve as an important regulator of MNB/DYRK1a expression and activity. Several other key organizers of the MT cytoskeleton, such as TPX2, XCTK2, NuMA, and GM130, also localize to the interphase nucleus (Walczak et al, 1997; Wei et al, 2015; Wiese et al, 2001; Wittmann et al, 1998; Wittmann et al, 2000). Strikingly, the binding of importin α or β to the NLS of these proteins prevents either their association with MTs, or their action upon MTs (Ems-McClung et al, 2004; Schatz et al, 2003; Wei et al, 2015; Wiese et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis

Ori-McKenney

McKenney

Huang

et al. 2016

Neuron

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SUMMARY Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASD). In a screen for abnormal dendrite development, we identified Minibrain(MNB)/DYRK1a, a kinase implicated in DS and ASD, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phospho-regulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of post-translational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis

Ori-McKenney

McKenney

Huang

et al. 2016

Neuron

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“…Cell-culture-based studies have implicated GM130 in a number of cellular processes in addition to secretory trafficking, including cytoskeletal regulation, which is important for cell migration and cell division (4,31,33,34). It was therefore surprising that the GM130 KO mice did not display any overt developmental phenotype; pups were born at normal weight and looked morphologically normal.…”

Section: Discussionmentioning

confidence: 99%

“…The Golgi apparatus lies at the heart of the secretory pathway and plays a critical role in the posttranslational modification and trafficking of secretory cargo proteins and lipids (1). In addition to these core functions, the Golgi apparatus also contributes to cell cycle regulation and cytoskeletal dynamics (2)(3)(4). The Golgi apparatus has a characteristic architecture, comprising one or more stacks of cisternae that in vertebrate cells are laterally connected to form the Golgi ribbon (5,6).…”

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confidence: 99%

“…One of the best-studied golgins, GM130 (also known as GOLGA2), contributes to Golgi ribbon morphology and can tether transport vesicles to facilitate endoplasmic reticulum (ER) to Golgi traffic (24)(25)(26)(27). It has also been implicated in Golgi positioning and cytoskeletal regulation (4,28) and can contribute to the organization of neuronal Golgi outposts, at least in Drosophila (13). However, the physiological importance and in vivo functions of GM130 have yet to be explored in a mammal.…”

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confidence: 99%

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Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice

Liu

Mei

et al. 2016

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

100

104

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The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.GM130 | Golgi apparatus | polarized secretion | Purkinje cell | ataxia

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“…Partitioning of these disassembled Golgi membranes is facilitated by the mitotic spindle, which carries essential Golgi proteins that are required to reorganize an intact ribbon structure in the daughter cells (14). Moreover, in early mitosis the Golgi matrix protein GM130 activates the spindle assembly factor TPX2 to locally promote microtubule (MT) nucleation and spindle formation, thereby linking Golgi membranes and the nascent spindle (15). This highly regulated sequence of ribbon unlinking, vesiculation, partitioning, and reassembly is unique to mammals, where the Golgi stacks are interconnected.…”

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confidence: 99%

Mitotic Golgi disassembly is required for bipolar spindle formation and mitotic progression

Guizzunti

Seemann

2016

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

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During mitosis, the mammalian Golgi vesiculates and, upon partitioning, reassembles in each daughter cell; however, it is not clear whether the disassembly process per se is important for partitioning or is merely an outcome of mitotic entry. Here, we show that Golgi vesiculation is required for progression to metaphase. To prevent Golgi disassembly, we expressed HRP linked to a Golgi-resident protein and acutely triggered the polymerization of 3,3′-diaminobenzidine (DAB) in the Golgi lumen. The DAB polymer does not affect interphase cell viability, but inhibits Golgi fragmentation by nocodazole and brefeldin A and also halts cells in early mitosis. The arrest is Golgi specific and does not occur when DAB is polymerized in the endosomes. Cells with a DAB polymer in the Golgi enter mitosis normally but arrest with an intact Golgi clustered at a monopolar spindle and an active spindle assembly checkpoint (SAC). Mitotic progression is restored upon centrosome depletion by the Polo-like kinase 4 inhibitor, centrinone, indicating that the link between the Golgi and the centrosomes must be dissolved to reach metaphase. These results demonstrate that Golgi disassembly is required for mitotic progression because failure to vesiculate the Golgi activates the canonical SAC. This requirement suggests that cells actively monitor Golgi integrity in mitosis.

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GM130 Regulates Golgi-Derived Spindle Assembly by Activating TPX2 and Capturing Microtubules

Cited by 92 publications

References 55 publications

Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis

Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis

Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice

Mitotic Golgi disassembly is required for bipolar spindle formation and mitotic progression

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