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Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles.

ABSTRACT: During macropinocytosis, cells remodel their morphologies for the uptake of extracellular matter. This endocytotic mechanism relies on the collapse and closure of precursory structures, which are propagating actin-based, ring-shaped vertical undulations at the dorsal (top) cell membrane, a.k.a. circular dorsal ruffles (CDRs). As such, CDRs are essential to a range of vital and pathogenic processes alike. Here we show, based on both experimental data and theoretical analysis, that CDRs are propagating fronts of actin polymerization in a bistable system. The theory relies on a novel mass-conserving reaction-diffusion model, which associates the expansion and contraction of waves to distinct counter-propagating front solutions. Moreover, the model predicts that under a change in parameters (for example, biochemical conditions) CDRs may be pinned and fluctuate near the cell boundary or exhibit complex spiral wave dynamics due to a wave instability. We observe both phenomena also in our experiments indicating the conditions for which macropinocytosis is suppressed.

SUBMITTER: Bernitt E

PROVIDER: S-EPMC5481797 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles.

Bernitt Erik E Döbereiner Hans-Günther HG Gov Nir S NS Yochelis Arik A

Nature communications 20170619

During macropinocytosis, cells remodel their morphologies for the uptake of extracellular matter. This endocytotic mechanism relies on the collapse and closure of precursory structures, which are propagating actin-based, ring-shaped vertical undulations at the dorsal (top) cell membrane, a.k.a. circular dorsal ruffles (CDRs). As such, CDRs are essential to a range of vital and pathogenic processes alike. Here we show, based on both experimental data and theoretical analysis, that CDRs are propag ...[more]

PMID: 28627511

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Project description:BackgroundDendrite morphogenesis plays an essential role in establishing the connectivity and receptive fields of neurons during the development of the nervous system. To generate the diverse morphologies of branched dendrites, neurons use external cues and cell surface receptors to coordinate intracellular cytoskeletal organization; however, the molecular mechanisms of how this signaling forms branched dendrites are not fully understood.MethodsWe performed in vivo time-lapse imaging of the PVD neuron in C. elegans in several mutants of actin regulatory proteins, such as the WAVE Regulatory Complex (WRC) and UNC-34 (homolog of Enabled/Vasodilator-stimulated phosphoprotein (Ena/VASP)). We examined the direct interaction between the WRC and UNC-34 and analyzed the localization of UNC-34 in vivo using transgenic worms expressing UNC-34 fused to GFP.ResultsWe identify a stereotyped sequence of morphological events during dendrite outgrowth in the PVD neuron in C. elegans. Specifically, local increases in width ("swellings") give rise to filopodia to facilitate a "rapid growth and pause" mode of growth. In unc-34 mutants, filopodia fail to form but swellings are intact. In WRC mutants, dendrite growth is largely absent, resulting from a lack of both swelling and filopodia formation. We also found that UNC-34 can directly bind to the WRC. Disrupting this binding by deleting the UNC-34 EVH1 domain prevented UNC-34 from localizing to swellings and dendrite tips, resulting in a stunted dendritic arbor and reduced filopodia outgrowth.ConclusionsWe propose that regulators of branched and linear F-actin cooperate to establish dendritic branches. By combining our work with existing literature, we propose that the dendrite guidance receptor DMA-1 recruits the WRC, which polymerizes branched F-actin to generate "swellings" on a mother dendrite. Then, WRC recruits the actin elongation factor UNC-34/Ena/VASP to initiate growth of a new dendritic branch from the swelling, with the help of the actin-binding protein UNC-115/abLIM. Extension of existing dendrites also proceeds via swelling formation at the dendrite tip followed by UNC-34-mediated outgrowth. Following dendrite initiation and extension, the stabilization of branches by guidance receptors further recruits WRC, resulting in an iterative process to build a complex dendritic arbor.

Dataset Information

Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles.

Publications

Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles.

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