Filopodia are required for cortical neurite initiation

“…As for the role of the actin cytoskeleton, although earlier work suggested that the actin depolymerizing drug cytochalasin D did not inhibit neurite formation in chick dorsal root ganglia neurons [40], more recent studies have demonstrated a critical role of the Ena/Mena/VASP family of proteins (abbreviated as Ena/VASP) in neurite formation [41,42]. Ena/VASP proteins regulate actin dynamics by antagonizing actin filament capping and promoting filament bundling [43,44].…”

Section: Introductionmentioning

confidence: 99%

“…Ena/VASP proteins regulate actin dynamics by antagonizing actin filament capping and promoting filament bundling [43,44]. In mice lacking all three Ena/VASP proteins, cortical neurons lacked filopodia and failed to initiate neurites, a process that can be rescued either by over-expression of the actin nucleating protein mDia2 or by plating neurons on the filopodia-promoting laminin substrate [41]. In another recent study, the actin depolarizing factor (ADF)/Cofilin family, which depolymerizes and severs actin filaments [45,46], was shown to promote neurite formation by driving actin retrograde flow and thereby allowing microtubule protrusion [47].…”

Section: Introductionmentioning

confidence: 99%

Actin Aggregations Mark the Sites of Neurite Initiation

et al. 2016

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A salient feature of neurons is their intrinsic ability to grow and extend neurites, even in the absence of external cues. Compared to the later stages of neuronal development, such as neuronal polarization and dendrite morphogenesis, the early steps of neuritogenesis remain relatively unexplored. Here we showed that redistribution of cortical actin into large aggregates preceded neuritogenesis and determined the site of neurite initiation. Enhancing actin polymerization by jasplakinolide treatment effectively blocked actin redistribution and neurite initiation, while treatment with the actin depolymerizing agents latrunculin A or cytochalasin D accelerated neurite formation. Together, these results demonstrate a critical role of actin dynamics and reorganization in neurite initiation. Further experiments showed that microtubule dynamics and protein synthesis are not required for neurite initiation, but are required for later neurite stabilization. The redistribution of actin during early neuronal development was also observed in the cerebral cortex and hippocampus in vivo.

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“…Neuritic sprouting starts at actin‐rich filopodial protrusions (Dent et al. 2007). To test whether the WIP contribution to neuron complexity was linked to this very early event, we quantified the number of neuritic filopodia and F‐actin patches (transient accumulations of F‐actin within the neuritic shaft which serve as precursors for neuritic filopodia [Loudon et al.…”

Section: Resultsmentioning

confidence: 99%

“…Filopodia are indispensable for neuritic initiation (Dent et al. 2007; Flynn 2013). The actin‐based filopodia first protrude, then MT follow the lead of the advancing filopodia that finally become elongating neurites.…”

Section: Discussionmentioning

confidence: 99%

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

Franco-Villanueva

Antón

2015

Brain and Behavior

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IntroductionNeuronal morphogenesis is governed mainly by two interconnected processes, cytoskeletal reorganization, and signal transduction. The actin‐binding molecule WIP (Wiskott‐Aldrich syndrome protein [WASP]‐interacting protein) was identified as a negative regulator of neuritogenesis. Although WIP controls activity of the actin‐nucleation‐promoting factor neural WASP (N‐WASP) during neuritic differentiation, its implication in signal transduction remains unknown.MethodsUsing primary neurons from WIP‐deficient and wild‐type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by WIP deficiency.ResultsHere, we describe the WIP contribution to the regulation of neuritic elaboration and ramification through modification in phosphorylation levels of several kinases that participate in the mammalian target of rapamycin complex 1 (mTORC1)‐p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. WIP deficiency induces an increase in the number of neuritic bifurcations and filopodial protrusions in primary embryonic neurons. This phenotype is not due to modifications in the activity of the phosphoinositide 3 kinase (PI3K)‐Akt pathway, but to reduced phosphorylation of the S6K residues Ser411 and Thr389. The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of WIP. Incubation of control neurons with pharmacological inhibitors of mTORC1 or Abl, two S6K regulators, conferred a morphology resembling that of WIP‐deficient neurons. Moreover, the preferential co‐distribution of phospho‐S6K with polymerized actin is altered in WIP‐deficient neurons.ConclusionThese experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.

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Filopodia are required for cortical neurite initiation

Cited by 294 publications

References 50 publications

Dendritic spine actin cytoskeleton in autism spectrum disorder

Dendritic spine actin cytoskeleton in autism spectrum disorder

Actin Aggregations Mark the Sites of Neurite Initiation

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

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