Calcineurin-dependent cofilin activation and increased retrograde actin flow drive 5-HT–dependent neurite outgrowth in<i>Aplysia</i>bag cell neurons

Zhang, Xiao-Feng; Hyland, Callen; Goor, David Van; Forscher, Paul

doi:10.1091/mbc.e12-10-0715

Cited by 36 publications

(61 citation statements)

References 89 publications

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“…8), a finding consistent with other studies that showed an increase in actin retrograde flow downstream of cofilin activation (51,56,57). Decrease of endogenous CIN by siRNA did not reduce retrograde flow, which one could have expected with lower levels of active cofilin.…”

Section: Discussionsupporting

confidence: 87%

Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels

Delorme-Walker

Seo

Gohla

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cofilin, a critical player of actin dynamics, is spatially and temporally regulated to control the direction and force of membrane extension required for cell locomotion. In carcinoma cells, although the signaling pathways regulating cofilin activity to control cell direction have been established, the molecular machinery required to generate the force of the protrusion remains unclear. We show that the cofilin phosphatase chronophin (CIN) spatiotemporally regulates cofilin activity at the cell edge to generate persistent membrane extension. We show that CIN translocates to the leading edge in a PI3-kinase-, Rac1-, and cofilindependent manner after EGF stimulation to activate cofilin, promotes actin free barbed end formation, accelerates actin turnover, and enhances membrane protrusion. In addition, we establish that CIN is crucial for the balance of protrusion/retraction events during cell migration. Thus, CIN coordinates the leading edge dynamics by controlling active cofilin levels to promote MTLn3 cell protrusion.ofilin is one crucial mediator of actin cytoskeletal dynamics during cell motility (1-5). At the cell edge, cofilin severs F-actin filaments, generating substrates for Arp2/3-mediated branching activity and contributing to F-actin depolymerization by creating a new pointed end and F-actin assembly by increasing the pool of polymerization-competent actin monomers (G-actin) (6, 7). Because of its ability to sever actin filaments and thus, modulate actin dynamics, the precise spatial and temporal regulation of cofilin activity at the cell leading edge is crucial to cell protrusion, chemotaxis, and motility both in vitro and in vivo (2,(8)(9)(10)(11)(12)(13). Misregulation of cofilin activity and/or expression is directly related to diseases, including tumor metastasis (14-18) and Alzheimer's disease (19).Several mechanisms regulate tightly the activation of cofilin in response to upstream stimuli, including interaction with phosphatidylinositol (4,5)-bisphosphate (20-22), local pH changes (23,24), and phosphorylation at a single regulatory serine (Ser3) (8,25). The phosphorylation of cofilin, leading to its inactivation, is catalyzed by two kinase families: the LIM-kinases [LIMKs(Lin11, Isl-1, and Mec-3 domain)] and the testicular kinases (25-27). Two primary families of ser/thr phosphatases dephosphorylate and reactivate the actin-depolymerizing and -severing functions of cofilin: slingshot (SSH) (28) and chronophin (CIN) (29).SSH was identified as a cofilin phosphatase through genetic studies in Drosophila (28). The most active and abundant SSH isoform, SSH-1L, has been implicated in such biological processes as cell division, growth cone motility/morphology, neurite extension, and actin dynamics during membrane protrusion (30). SSH dephosphorylates a number of actin regulatory proteins in addition to cofilin, including LIMK1 (31) and Coronin 1B (32). CIN is a haloacid dehydrogenase-type phosphatase, a family of enzymes with activity in mammalian cells that has been poorly characterized. CIN dephosph...

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Section: Discussionsupporting

confidence: 87%

Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels

Delorme-Walker

Seo

Gohla

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…We thus measured the retrograde flow of activated PA-GFP-actin in lamellipodia before and after irradiation of cofilin-KR (Figure 4A). Consistent with other results showing that cofilin activation increases retrograde flow (Delorme et al ., 2007; Zhang et al ., 2012), we saw a marked increase in flow rate when cells were overexpressing constitutively active cofilin S3A , which was significantly reduced by ∼44% (56 ± 4.0 to 37 ± 3.5 nm/s) after CALI (Figure 4, B and C). In cells expressing either cofilin-KR or KR alone, no change was observed after CALI; there was a slight increase in retrograde flow speed after CALI of cofilin S3E -KR (Figure 4C).…”

Section: Resultsmentioning

confidence: 99%

“…This finding is consistent with a recent study demonstrating an essential role for ADF/cofilin in regulating retrograde flow in neurogenesis (Flynn et al ., 2012) and other studies showing an increase in retrograde flow downstream of cofilin activation (Delorme et al ., 2007; Zhang et al ., 2012). Of importance, the decrease in retrograde flow rate suggests that the increase of F-actin at the back of the lamellipodia actin network after cofilin CALI is not simply a result of more F-actin being moved backward but instead is caused by loss of filament disassembly.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro it has been shown that filament severing by cofilin stochastically alters filament dynamics to favor turnover (Michelot et al ., 2007) and can turn over branched actin networks in bulk (Reymann et al ., 2011). Increasing the dynamic nature of the actin network in lamellipodia downstream of cofilin activity via enhanced filament turnover and retrograde flow appears to be important for protrusion formation and cell motility (Hotulainen et al ., 2005; Delorme et al ., 2007; Zhang et al ., 2012), although the inverse has also been shown during growth cone guidance (Wen et al ., 2007). The differences here may lie in the amount of cofilin activation and specific context in which it is activated.…”

Section: Discussionmentioning

confidence: 99%

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Instantaneous inactivation of cofilin reveals its function of F-actin disassembly in lamellipodia

Vitriol

Wise

Berginski

et al. 2013

MBoC

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“…Microtubules (MTs) and actin microfilaments have been implicated in neurite outgrowth, with many studies focusing on the growth cone at the tip of the axon. Previous models suggest that the driving forces for neurite outgrowth are MT polymerization and the treadmilling of F-actin (1,2). However, other studies demonstrate that F-actin is dispensable to outgrowth and neurites extend even in the absence of F-actin (3)(4)(5).…”

mentioning

confidence: 99%

Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

Winding

Kelliher

Lü

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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The plus-end microtubule (MT) motor kinesin-1 is essential for normal development, with key roles in the nervous system. Kinesin-1 drives axonal transport of membrane cargoes to fulfill the metabolic needs of neurons and maintain synapses. We have previously demonstrated that kinesin-1, in addition to its well-established role in organelle transport, can drive MT-MT sliding by transporting "cargo" MTs along "track" MTs, resulting in dramatic cell shape changes. The mechanism and physiological relevance of this MT sliding are unclear. In addition to its motor domain, kinesin-1 contains a second MT-binding site, located at the C terminus of the heavy chain. Here, we mutated this C-terminal MT-binding site such that the ability of kinesin-1 to slide MTs is significantly compromised, whereas cargo transport is unaffected. We introduced this mutation into the genomic locus of kinesin-1 heavy chain (KHC), generating the Khc mutA allele. Khc mutA neurons displayed significant MT sliding defects while maintaining normal transport of many cargoes. Using this mutant, we demonstrated that MT sliding is required for axon and dendrite outgrowth in vivo. Consistent with these results, Khc mutA flies displayed severe locomotion and viability defects. To test the role of MT sliding further, we engineered a chimeric motor that actively slides MTs but cannot transport organelles. Activation of MT sliding in Khc mutA neurons using this chimeric motor rescued axon outgrowth in cultured neurons and in vivo, firmly establishing the role of sliding in axon outgrowth. These results demonstrate that MT sliding by kinesin-1 is an essential biological phenomenon required for neuronal morphogenesis and normal nervous system development.kinesin-1 | microtubules | Drosophila | axon outgrowth | dendrite outgrowth N eurons are the basic unit of the nervous system, forming vast networks throughout the body that communicate using receptorligand machinery located in long cellular projections called axons and dendrites. Learning how these processes form is key to understanding the early development and pathology of the nervous system. Microtubules (MTs) and actin microfilaments have been implicated in neurite outgrowth, with many studies focusing on the growth cone at the tip of the axon. Previous models suggest that the driving forces for neurite outgrowth are MT polymerization and the treadmilling of F-actin (1, 2). However, other studies demonstrate that F-actin is dispensable to outgrowth and neurites extend even in the absence of F-actin (3-5).Our group has found that the motor protein kinesin-1 can rearrange the MT network by sliding MTs against each other (6). We have shown that kinesin-1 is required for MT sliding in cultured neurons and kinesin-1 depletion inhibits both neurite outgrowth and regeneration (7,8). Additionally, we have observed MT sliding in axons as well as MTs pushing on the axon tip (9). Recent studies from other groups have also implicated MT translocation in axon extension and dendritic organization (10-12). Based on th...

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Calcineurin-dependent cofilin activation and increased retrograde actin flow drive 5-HT–dependent neurite outgrowth inAplysiabag cell neurons

Cited by 36 publications

References 89 publications

Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels

Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels

Instantaneous inactivation of cofilin reveals its function of F-actin disassembly in lamellipodia

Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

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