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Tau co-organizes dynamic microtubule and actin networks.

ABSTRACT: The crosstalk between microtubules and actin is essential for cellular functions. However, mechanisms underlying the microtubule-actin organization by cross-linkers remain largely unexplored. Here, we report that tau, a neuronal microtubule-associated protein, binds to microtubules and actin simultaneously, promoting in vitro co-organization and coupled growth of both networks. By developing an original assay to visualize concomitant microtubule and actin assembly, we show that tau can induce guided polymerization of actin filaments along microtubule tracks and growth of single microtubules along actin filament bundles. Importantly, tau mediates microtubule-actin co-alignment without changing polymer growth properties. Mutagenesis studies further reveal that at least two of the four tau repeated motifs, primarily identified as tubulin-binding sites, are required to connect microtubules and actin. Tau thus represents a molecular linker between microtubule and actin networks, enabling a coordination of the two cytoskeletons that might be essential in various neuronal contexts.

SUBMITTER: Elie A

PROVIDER: S-EPMC4421749 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Tau co-organizes dynamic microtubule and actin networks.

Elie Auréliane A Prezel Elea E Guérin Christophe C Denarier Eric E Ramirez-Rios Sacnicte S Serre Laurence L Andrieux Annie A Fourest-Lieuvin Anne A Blanchoin Laurent L Arnal Isabelle I

Scientific reports 20150505

The crosstalk between microtubules and actin is essential for cellular functions. However, mechanisms underlying the microtubule-actin organization by cross-linkers remain largely unexplored. Here, we report that tau, a neuronal microtubule-associated protein, binds to microtubules and actin simultaneously, promoting in vitro co-organization and coupled growth of both networks. By developing an original assay to visualize concomitant microtubule and actin assembly, we show that tau can induce gu ...[more]

PMID: 25944224

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Project description:Proper organization and dynamics of the actin and microtubule (MT) cytoskeleton are essential for growth cone behaviors during axon growth and guidance. The MT-associated protein tau is known to mediate actin/MT interactions in cell-free systems but the role of tau in regulating cytoskeletal dynamics in living neurons is unknown. We used cultures of cortical neurons from postnatal day (P)0-P2 golden Syrian hamsters (Mesocricetus auratus) of either sex to study the role of tau in the organization and dynamics of the axonal growth cone cytoskeleton. Here, using super resolution microscopy of fixed growth cones, we found that tau colocalizes with MTs and actin filaments and is also located at the interface between actin filament bundles and dynamic MTs in filopodia, suggesting that tau links these two cytoskeletons. Live cell imaging in concert with shRNA tau knockdown revealed that reducing tau expression disrupts MT bundling in the growth cone central domain, misdirects trajectories of MTs in the transition region and prevents single dynamic MTs from extending into growth cone filopodia along actin filament bundles. Rescue experiments with human tau expression restored MT bundling, MT penetration into the growth cone periphery and close MT apposition to actin filaments in filopodia. Importantly, we found that tau knockdown reduced axon outgrowth and growth cone turning in Wnt5a gradients, likely due to disorganized MTs that failed to extend into the peripheral domain and enter filopodia. These results suggest an important role for tau in regulating cytoskeletal organization and dynamics during growth cone behaviors.SIGNIFICANCE STATEMENT Growth cones are the motile tips of growing axons whose guidance behaviors require interaction of the dynamic actin and microtubule cytoskeleton. Tau is a microtubule-associated protein that stabilizes microtubules in neurons and in cell-free systems regulates actin-microtubule interaction. Here, using super resolution microscopy, live-cell imaging, and tau knockdown, we show for the first time in living axonal growth cones that tau is important for microtubule bundling and microtubule exploration of the actin-rich growth cone periphery. Importantly tau knockdown reduced axon outgrowth and growth cone turning, due to disorganized microtubules that fail to enter filopodia and co-align with actin filaments. Understanding normal tau functions will be important for identifying mechanisms of tau in neurodegenerative diseases such as Alzheimer's.

Project description:Selective cargo transport into axons and dendrites over the microtubule network is essential for neuron polarization. The axon initial segment (AIS) separates the axon from the somatodendritic compartment and controls the microtubule-dependent transport into the axon. Interestingly, the AIS has a characteristic microtubule organization; it contains bundles of closely spaced microtubules with electron dense cross-bridges, referred to as microtubule fascicles. The microtubule binding protein TRIM46 localizes to the AIS and when overexpressed in non-neuronal cells forms microtubule arrays that closely resemble AIS fascicles in neurons. However, the precise role of TRIM46 in microtubule fasciculation in neurons has not been studied. Here we developed a novel correlative light and electron microscopy approach to study AIS microtubule organization. We show that in cultured rat hippocampal neurons of both sexes, TRIM46 levels steadily increase at the AIS during early neuronal differentiation and at the same time closely spaced microtubules form, whereas the fasciculated microtubules appear at later developmental stages. Moreover, we localized TRIM46 to the electron dense cross-bridges and show that depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing. These data indicate that TRIM46 has an essential role in organizing microtubule fascicles in the AIS.SIGNIFICANCE STATEMENT The axon initial segment (AIS) is a specialized region at the proximal axon where the action potential is initiated. In addition the AIS separates the axon from the somatodendritic compartment, where it controls protein transport to establish and maintain neuron polarity. Cargo vesicles destined for the axon recognize specialized microtubule tracks that enter the AIS. Interestingly the microtubules entering the AIS form crosslinked bundles, called microtubule fascicules. Recently we found that the microtubule-binding protein TRIM46 localizes to the AIS, where it may organize the AIS microtubules. In the present study we developed a novel correlative light and electron microscopy approach to study the AIS microtubules during neuron development and identified an essential role for TRIM46 in microtubule fasciculation.

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Tau co-organizes dynamic microtubule and actin networks.

Publications

Tau co-organizes dynamic microtubule and actin networks.

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