Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons

Moradi, Mehri; Sivadasan, Rajeeve; Saal, Lena; Lüningschrör, Patrick; Dombert, Benjamin; Rathod, Reena Jagdish; Dieterich, Daniela C.; Blum, Robert; Sendtner, Michael

doi:10.1083/jcb.201604117

Cited by 56 publications

(68 citation statements)

References 90 publications

(131 reference statements)

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“…C9ORF72 modulates the activity of the small GTPases, resulting in increased activity of LIM kinases 1 and 2 and regulation of axonal actin dynamics (Sivadasan et al, 2016). Various actin isoforms are expressed in primary mouse MNs, and their transcripts have been observed to be translocated into axons (Moradi et al, 2017). It is proposed that short hairpin RNA-mediated depletion of α-actin reduces axonal filopodia dynamics and disrupts collateral branch formation in developing MNs (Moradi et al, 2017).…”

Section: Aberrant Axonal Branchingmentioning

confidence: 99%

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

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Section: Aberrant Axonal Branchingmentioning

confidence: 99%

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

et al. 2020

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“…In fibroblasts, knockdown and over-expression of β-actin reduces and enhances cell motility (Bunnell et al, 2011;Peckham et al, 2001), respectively, whereas γ-actin is not required for migration (Bunnell and Ervasti, 2010). In motor neurons, knockdown of β-actin reduces growth cone size and motility, whereas γ-actin-depleted neurons have normal axonal outgrowth, but display a reduction in axonal filopodia dynamics (Moradi et al, 2017). β-actin has also been found to be the more prevalent isoform in the G-actin pool (Kapustina et al, 2016), and β-actin knockouts in mouse embryonic fibroblasts have been shown to lead to decreased ratios of G-to F-actin (Bunnell et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…However, it is important to stress that the observed functional distinctions between the isoforms are general trends (Flamholz et al, 2014) and, to some degree, the actin isoforms can compensate for each other. This is evidenced in experiments showing an upregulation of αand γ-actin in response to β-actin depletion (Moradi et al, 2017), or the downregulation of endogenous βand γ-actin genes in response to exogenously expressed γ-actin (Lloyd et al, 1992) to maintain overall cellular actin levels.…”

Section: Introductionmentioning

confidence: 99%

“…The actin monomer-binding myocardin transcriptional coactivator (MAL, also known as MYOCD) and serum response factor (SRF) complex (MAL-SRF) is one such regulator of this feedback loop (Salvany et al, 2014). β-actin-encoding mRNA has been found at the leading edge of fibroblasts (Ross et al, 1997), and to localize to neuronal growth cones (Leung et al, 2006;Moradi et al, 2017;Zhang et al, 2001) and dendritic spines (Tiruchinapalli et al, 2003). The specific mRNA localization is regulated by an additional sequence in the 3′ untranslated region (UTR) of β-actin that interacts with zipcode-binding protein (ZBP1; also known as IGF2BP1), which controls the targeting and regulated translation of mRNA transcripts (Ross et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Reconsidering an active role for G-actin in cytoskeletal regulation

Skruber

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Vitriol

2018

Journal of Cell Science

125

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Globular (G)-actin, the actin monomer, assembles into polarized filaments that form networks that can provide structural support, generate force and organize the cell. Many of these structures are highly dynamic and to maintain them, the cell relies on a large reserve of monomers. Classically, the G-actin pool has been thought of as homogenous. However, recent work has shown that actin monomers can exist in distinct groups that can be targeted to specific networks, where they drive and modify filament assembly in ways that can have profound effects on cellular behavior. This Review focuses on the potential factors that could create functionally distinct pools of actin monomers in the cell, including differences between the actin isoforms and the regulation of G-actin by monomer binding proteins, such as profilin and thymosin β4. Owing to difficulties in studying and visualizing G-actin, our knowledge over the precise role that specific actin monomer pools play in regulating cellular actin dynamics remains incomplete. Here, we discuss some of these unanswered questions and also provide a summary of the methodologies currently available for the imaging of G-actin.

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“…Together, these RNA-seq data sets, as well as others now emerging (Rotem and others 2017), will bring new perspectives on how mRNA transport varies between different neuronal types, different physiological conditions, and disease states (Figure 1). For example, Moradi et al (2017) recently showed that axonally translated γ- and α-actin regulate different growth morphologies than β-actin in motor axons, while γ-actin mRNA is excluded from sensory and cortical axons (Moradi and others 2017). …”

Section: Introductionmentioning

confidence: 99%

Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease

2017

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Intra-axonal protein synthesis has been shown to play critical roles in both development and repair of axons. Axons provide long-range connectivity in the nervous system, and disruption of their function and/or structure is seen in several neurological diseases and disorders. Axonally synthesized proteins or losses in axonally synthesized proteins contribute to neurodegenerative diseases, neuropathic pain, viral transport, and survival of axons. Increasing sensitivity of RNA detection and quantitation coupled with methods to isolate axons to purity has shown that a surprisingly complex transcriptome exists in axons. This extends across different species, neuronal populations, and physiological conditions. These studies have helped to define the repertoire of neuronal mRNAs that can localize into axons and imply previously unrecognized functions for local translation in neurons. Here, we review the current state of transcriptomics studies of isolated axons, contrast axonal mRNA profiles between different neuronal types and growth states, and discuss how mRNA transport into and translation within axons contribute to neurological disorders.

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Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons

Cited by 56 publications

References 90 publications

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

Reconsidering an active role for G-actin in cytoskeletal regulation

Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease

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