The podocyte cytoskeleton in health and in disease

Mathieson, Peter W.

doi:10.1093/ckj/sfs153

Cited by 18 publications

(14 citation statements)

References 30 publications

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“…These proteins are involved in actin organization in podocytes and the mutations results in FP effacement. Thus, it has become ever clearer that the precise organization and regulation of the actin cytoskeleton in podocytes is essential for the maintenance of normal structure and function and the actin cytoskeleton serves as the common final pathway organizing FP effacement, independent of the cause of podocyte damage [ 12 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Marusugi

Nakano

Sasaki

et al. 2016

The Journal of Veterinary Medical Science

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Podocytes are terminally differentiated and highly specialized cells in the glomerulus, and they form a crucial component of the glomerular filtration barrier. The ICGN mouse is a model of glomerular dysfunction that shows gross morphological changes in the podocyte foot process, accompanied by proteinuria. Previously, we demonstrated that proteinuria in ICR-derived glomerulonephritis mouse ICGN mice might be caused by a deletion mutation in the tensin2 (Tns2) gene (designated Tns2nph). To test whether this mutation causes the mutant phenotype, we created knockout (KO) mice carrying a Tns2 protein deletion in the C-terminal Src homology and phosphotyrosine binding (SH2-PTB) domains (designated Tns2ΔC) via CRISPR/Cas9-mediated genome editing. Tns2nph/Tns2ΔC compound heterozygotes and Tns2ΔC/Tns2ΔC homozygous KO mice displayed podocyte abnormalities and massive proteinuria similar to ICGN mice, indicating that these two mutations are allelic. Further, this result suggests that the SH2-PTB domain of Tns2 is required for podocyte integrity. Tns2 knockdown in a mouse podocyte cell line significantly enhanced actin stress fiber formation and cell migration. Thus, this study provides evidence that alteration of actin remodeling resulting from Tns2 deficiency causes morphological changes in podocytes and subsequent proteinuria.

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Section: Discussionmentioning

confidence: 99%

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Marusugi

Nakano

Sasaki

et al. 2016

The Journal of Veterinary Medical Science

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“…Without the in vivo mechanical stimuli and the final shape signals, cultured podocytes present geometric characteristics (e.g., surface-to-volume ratio, eccentricity, characteristic length, etc.) that are clearly different from the in vivo structure (10,11). Consequently, it is known that protein localization, gene expression levels, and active signaling pathways in cultured podocytes are not similar those of the in vivo system.…”

Section: Introductionmentioning

confidence: 87%

Chaotic propagation of spatial cytoskeletal instability modulates integrity of podocyte foot processes

Falkenberg

Azeloglu

Stothers

et al. 2016

Preprint

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The kidney podocyte's function depends on its distinctive morphology. Each podocyte has fingerlike projections, called foot processes, that interdigitate with the processes of neighboring cells to form the glomerular filtration barrier. The integrity of foot process interactions depends on tight spatial control of the dynamics of the underlying actin cytoskeleton, which is regulated by the GTPases, Rac1 and RhoA. To understand how spatially-specific regulation of actin filament dynamics within foot processes controls local morphology, we used a combination of 3-D microscopy and dynamical models. We experimentally determined cell-cell interactions using serial blockface scanning electron microscopy and reconstructed a 3-D spatial representation of a podocyte. We developed a minimal dynamical system for regulation of the actin cytoskeleton; using this 3-D model, we determined how spatial reaction-diffusion dynamics can dysregulate actin bundling, leading to propagation of chaotic foot process effacement. Consistent with experimental observations, our simulations predicted that hyperactive RhoA could destabilize the cytoskeleton. Our simulations showed that deleterious mechanochemical stimuli could lead to local heterogeneity of cytoskeletal dynamics resulting in the emergence of progressive and chaotic loss of foot processes. While global enhancement of Rac1 may result in stronger bundles, the spatial simulations showed that even transient local heterogeneities in polymerization could have dramatic consequences in the stability of multiple foot processes. We conclude that the podocyte morphology optimized for filtration contains intrinsic fragility whereby local imbalances in biochemical and biophysical reactions lead to morphological changes associated with glomerular pathophysiology.

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“…The precise spatial and temporal co-ordination of these functions is fundamental for the movement of cells that is required for many biological events ranging from organ development to tissue repair. The importance of actin cytoskeleton dynamics is emphasised by the onset and progress of diseases due to cells lacking or expressing mutated variants of actin-associated proteins (Mathieson, 2012;Ramaekers and Bosman, 2004). In spite of several studies, the functions of some actin-associated proteins have not been well defined.…”

Section: Introductionmentioning

confidence: 99%

LSP1-myosin1e bi-molecular complex regulates focal adhesion dynamics and cell migration

Schaeringer

Maxeiner

Schalla

et al. 2020

Preprint

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Telephone: +49 241 8085248Running head: LSP1-myosin1e complex regulates cell migration. Abstract Several cytoskeleton-associated proteins and signalling pathways work in concert to regulate actin cytoskeleton remodelling, cell adhesion and migration. We have recently demonstrated that the bi-molecular complex between the leukocyte-specific protein 1 (LSP1) and myosin1e controls actin cytoskeleton remodelling during phagocytosis. In this study, we show that LSP1 down regulation severely impairs cell migration, lamellipodia formation and focal adhesion dynamics in macrophages.Inhibition of the interaction between LSP1 and myosin1e also impairs these processes resulting in poorly motile cells, which are characterised by few and small lamellipodia.Furthermore, cells in which LSP1-myosin1e interaction is inhibited are typically associated with inefficient focal adhesion turnover. Collectively, our findings show that the LSP1-myosin1e bimolecular complex plays a pivotal role in the regulation of actin cytoskeleton remodelling and focal adhesion dynamics required for cell migration.

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The podocyte cytoskeleton in health and in disease

Cited by 18 publications

References 30 publications

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing

Chaotic propagation of spatial cytoskeletal instability modulates integrity of podocyte foot processes

LSP1-myosin1e bi-molecular complex regulates focal adhesion dynamics and cell migration

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