The Role of Local Actin Instability in Axon Formation

Bradke, Frank; Dotti, Carlos G.

doi:10.1126/science.283.5409.1931

Cited by 475 publications

(417 citation statements)

References 30 publications

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“…Neuron polarization consists of morphological polarization that involve preferential elongation of the axon; sorting of proteins in different compartments; and functional polarization, in which the AIS barrier is also involved. It is a very complex phenomenon that requires local destabilization of actin 62 and local stabilization of MTs 63 . RhoA activation is known to decrease actin turnover, stabilizing actin, and thus participating in axon retraction 64 .…”

Section: Discussionmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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Section: Discussionmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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“…In LatA-treated neurons, the fluorescent phalloidin staining was strongly decreased, and filamentous actin appeared fragmented, scattered in spots in the cell bodies and along neurites ( Figure 10A, LatA). In control and wt ␣-synuclein neurons a loss of filamentous actin staining was evident at the tips of the neurites, where actin remodeling is more active and more sensitive to the action of LatA (Bradke and Dotti, 1999). On the contrary, the A30P ␣-synuclein neurons treated with LatA exhibited filamentous actin concentrated in small foci, particularly visible along the neuritic processes at their proximal regions, where A30P ␣-synuclein was also enriched.…”

Section: ␣-Synuclein Is An Actin Modulatormentioning

confidence: 94%

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Sousa

Bellani

Giannandrea

et al. 2009

MBoC

104

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The function of ␣-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, ␣-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that ␣-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type ␣-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant ␣-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant ␣-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo-and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the ␣-synuclein gene, electroporation of wild-type ␣-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P ␣-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, ␣-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.

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“…Tiam1 is expressed at high levels in the developing brain (Habets et al, 1995), and its overexpression promotes lamellar spreading and neurite formation in neuroblastoma cells (van Leeuwen et al, 1997). Because one of the early events during neuronal polarization appears to involve the regulation of actin organization and dynamics by Rho-GTPases (Bradke and Dotti, 1999), it may well be that factors such as Tiam1 have an active participation in this event.…”

Section: Abstract: Tiam1; Microtubules; Microfilaments; Axons; Growtmentioning

confidence: 99%

Evidence for the Involvement of Tiam1 in Axon Formation

et al. 2001

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In cultured neurons, axon formation is preceded by the appearance in one of the multiple neurites of a large growth cone containing a labile actin network and abundant dynamic microtubules. The invasion-inducing T-lymphoma and metastasis 1 (Tiam1) protein that functions as a guanosine nucleotide exchange factor for Rac1 localizes to this neurite and its growth cone, where it associates with microtubules. Neurons overexpressing Tiam1 extend several axon-like neurites, whereas suppression of Tiam1 prevents axon formation, with most of the cells failing to undergo changes in growth cone size and in cytoskeletal organization typical of prospective axons. Cytochalasin D reverts this effect leading to multiple axon formation and penetration of microtubules within neuritic tips devoid of actin filaments. Taken together, these results suggest that by regulating growth cone actin organization and allowing microtubule invasion within selected growth cones, Tiam1 promotes axon formation and hence participates in neuronal polarization.

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The Role of Local Actin Instability in Axon Formation

Cited by 475 publications

References 30 publications

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Evidence for the Involvement of Tiam1 in Axon Formation

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