The Golgi Outpost Protein TPPP Nucleates Microtubules and Is Critical for Myelination

Fu, Meng‐meng; McAlear, Thomas S; Nguyen, Huy; Oses-Prieto, Juan; Valenzuela, Alex; Shi, Rebecca; Perrino, John; Huang, Ting‐Ting; Burlingame, Alma L.; Bechstedt, Susanne; Barres, Ben A.

doi:10.1016/j.cell.2019.08.025

Cited by 103 publications

(119 citation statements)

References 78 publications

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“…In some cell types, the Golgi complex recruits nucleation sites [21,22], and small Golgi outposts can be found in both mammalian and Drosophila dendrites [23,24]. Thus, it was proposed that the Golgi might act as a noncentrosomal MTOC in dendrites [25].…”

Section: Plos Biologymentioning

confidence: 99%

Endosomal Wnt signaling proteins control microtubule nucleation in dendrites

et al. 2020

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Dendrite microtubules are polarized with minus-end-out orientation in Drosophila neurons. Nucleation sites concentrate at dendrite branch points, but how they localize is not known. Using Drosophila, we found that canonical Wnt signaling proteins regulate localization of the core nucleation protein γTubulin (γTub). Reduction of frizzleds (fz), arrow (low-density lipoprotein receptor-related protein [LRP] 5/6), dishevelled (dsh), casein kinase Iγ, G proteins, and Axin reduced γTub-green fluorescent protein (GFP) at branch points, and two functional readouts of dendritic nucleation confirmed a role for Wnt signaling proteins. Both dsh and Axin localized to branch points, with dsh upstream of Axin. Moreover, tethering Axin to mitochondria was sufficient to recruit ectopic γTub-GFP and increase microtubule dynamics in dendrites. At dendrite branch points, Axin and dsh colocalized with early endosomal marker Rab5, and new microtubule growth initiated at puncta marked with fz, dsh, Axin, and Rab5. We propose that in dendrites, canonical Wnt signaling proteins are housed on early endosomes and recruit nucleation sites to branch points. OPEN ACCESS Citation: Weiner AT, Seebold DY, Torres-Gutierrez P, Folker C, Swope RD, Kothe GO, et al. (2020) Endosomal Wnt signaling proteins control microtubule nucleation in dendrites. PLoS Biol 18 (3): e3000647. https://doi.

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Section: Plos Biologymentioning

confidence: 99%

Endosomal Wnt signaling proteins control microtubule nucleation in dendrites

et al. 2020

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“…Further studies will be required to determine the in vivo linc00899-protein interactome and the relevance of these interactions in TPPP transcriptional regulation and cell division. TPPP is crucial for microtubule organisation in the brain and for local microtubule nucleation and myelin sheath elongation 65 . In Drosophila, TPPP mutants (also known as Ringmaker) exhibit defects in axonal extension 66 .…”

Section: Discussionmentioning

confidence: 99%

A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division

et al. 2020

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Genome stability relies on proper coordination of mitosis and cytokinesis, where dynamic microtubules capture and faithfully segregate chromosomes into daughter cells. With a high-content RNAi imaging screen targeting more than 2,000 human lncRNAs, we identify numerous lncRNAs involved in key steps of cell division such as chromosome segregation, mitotic duration and cytokinesis. Here, we provide evidence that the chromatin-associated lncRNA, linc00899, leads to robust mitotic delay upon its depletion in multiple cell types. We perform transcriptome analysis of linc00899-depleted cells and identify the neuronal microtubule-binding protein, TPPP/p25, as a target of linc00899. We further show that linc00899 binds TPPP/p25 and suppresses its transcription. In cells depleted of linc00899, upregulation of TPPP/p25 alters microtubule dynamics and delays mitosis. Overall, our comprehensive screen uncovers several lncRNAs involved in genome stability and reveals a lncRNA that controls microtubule behaviour with functional implications beyond cell division.

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“…The second and related reason to pursue the defect in dendrite morphology exhibited by myosin 18Aα knockdown/knockout Purkinje neurons is the published evidence that myosin 18A interacts with the resident Golgi protein GOLPH3 to promote the ribbon-like morphology of the Golgi apparatus in tissue culture cells (Dippold et al, 2009). Adding to the intrigue is the recent report that endogenous myosin 18A is present on Golgi outposts in oligodendrocytes (Fu et al, 2019). Together, these observations suggest that the defect in primary dendrite number exhibited by Purkinje neurons lacking myosin 18Aα, as well as other possible defects in dendrite morphology that might be revealed upon more extensive analyses, could be due to a defect in the localization and/or function of Golgi outposts and satellites.…”

Section: Discussionmentioning

confidence: 99%

Myosin 18Aα targets guanine nucleotide exchange factor β-Pix to dendritic spines of cerebellar Purkinje neurons to promote spine maturation

Alexander

Barzik

Fujiwara

et al. 2020

Preprint

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Dendritic spines are signaling microcompartments that serve as the primary site of synapse formation in neurons. Actin assembly and myosin 2 contractility play major roles in the maturation of spines from filopodial precursors, as well as in the subsequent, activitydependent changes in spine morphology that underly learning and memory. Myosin 18A is a myosin 2-like protein conserved from flies to man that lacks motor activity, is sub-stochiometric to myosin 2, and co-assembles with myosin 2 to make mixed filaments. Myosin 18A is alternatively spliced to create multiple isoforms that contain unique N-and C-terminal extensions harboring both recognizable and uncharacterized protein: protein interaction domains. These observations suggest that myosin 18A serves to recruit proteins to mixed filaments of myosin 2 and myosin 18A. One protein known to bind to myosin 18A is β-Pix, a guanine nucleotide exchange factor (GEF) for Rac1 and Cdc42. Notably, β-Pix has been shown to promote spine maturation by activating both Arp2/3 complex-dependent branched actin filament assembly and myosin 2 contractility within spines. Here we show that myosin 18A⍺ is expressed in cerebellar Purkinje neurons and concentrates in spines along with myosin 2 and Factin. Myosin 18A⍺ is targeted to spines by co-assembling with myosin 2 and by an actin binding site present in its N-terminal extension. miRNA-mediated knockdown of myosin 18A⍺ results in a significant defect in spine maturation that is rescued by an RNAi-immune version of myosin 18A⍺. Importantly, β-Pix co-localizes with myosin 18A⍺ in spines, and its spine localization is lost upon myosin 18A⍺ knockdown or when its myosin 18A⍺ binding site is deleted. Finally, we show that the spines of myosin 18A⍺ knockdown Purkinje neurons contain significantly less F-actin and myosin 2. Together, these data demonstrate that mixed filaments of myosin 2 and myosin 18A⍺ form a complex with β-Pix in Purkinje neuron spines that promotes spine maturation by enhancing the assembly of actin and myosin filaments downstream of β-Pix's GEF activity.

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The Golgi Outpost Protein TPPP Nucleates Microtubules and Is Critical for Myelination

Cited by 103 publications

References 78 publications

Endosomal Wnt signaling proteins control microtubule nucleation in dendrites

Endosomal Wnt signaling proteins control microtubule nucleation in dendrites

A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division

Myosin 18Aα targets guanine nucleotide exchange factor β-Pix to dendritic spines of cerebellar Purkinje neurons to promote spine maturation

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