PT  - JOURNAL ARTICLE
AU  - Cibele V. Falkenberg
AU  - Evren U. Azeloglu
AU  - Mark Stothers
AU  - Thomas J. Deerinck
AU  - Yibang Chen
AU  - John C. He
AU  - Mark H. Ellisman
AU  - James C. Hone
AU  - Ravi Iyengar
AU  - Leslie M. Loew
TI  - Chaotic propagation of spatial cytoskeletal instability modulates integrity of podocyte foot processes
AID  - 10.1101/065839
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 065839
4099  - http://biorxiv.org/content/early/2016/07/26/065839.short
4100  - http://biorxiv.org/content/early/2016/07/26/065839.full
AB  - 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.