Synaptopodin regulates the actin-bundling activity of α-actinin in an isoform-specific manner
Katsuhiko Asanuma, … , Jochen Reiser, Peter Mundel
Katsuhiko Asanuma, … , Jochen Reiser, Peter Mundel
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1188-1198. https://doi.org/10.1172/JCI23371.
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Article Cell biology

Synaptopodin regulates the actin-bundling activity of α-actinin in an isoform-specific manner

Abstract

Synaptopodin is the founding member of a novel class of proline-rich actin-associated proteins highly expressed in telencephalic dendrites and renal podocytes. Synaptopodin-deficient (synpo–/–) mice lack the dendritic spine apparatus and display impaired activity-dependent long-term synaptic plasticity. In contrast, the ultrastructure of podocytes in synpo–/– mice is normal. Here we show that synpo–/– mice display impaired recovery from protamine sulfate–induced podocyte foot process (FP) effacement and LPS-induced nephrotic syndrome. Similarly, synpo–/– podocytes show impaired actin filament reformation in vitro. We further demonstrate that synaptopodin exists in 3 isoforms, neuronal Synpo-short (685 AA), renal Synpo-long (903 AA), and Synpo-T (181 AA). The C terminus of Synpo-long is identical to that of Synpo-T. All 3 isoforms specifically interact with α-actinin and elongate α-actinin–induced actin filaments. synpo–/– mice lack Synpo-short and Synpo-long expression but show an upregulation of Synpo-T protein expression in podocytes, though not in the brain. Gene silencing of Synpo-T abrogates stress-fiber formation in synpo–/– podocytes, demonstrating that Synpo-T serves as a backup for Synpo-long in synpo–/– podocytes. In concert, synaptopodin regulates the actin-bundling activity of α-actinin in highly dynamic cell compartments, such as podocyte FPs and the dendritic spine apparatus.

Authors

Katsuhiko Asanuma, Kwanghee Kim, Jun Oh, Laura Giardino, Sophie Chabanis, Christian Faul, Jochen Reiser, Peter Mundel

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Synaptopodin colocalizes with α-actinin in tissues and cultured cells. (...
Synaptopodin colocalizes with α-actinin in tissues and cultured cells. (A) In the adult kidney, synaptopodin colocalizes with α-actinin-4 in podocytes (magnification, ×650). (B) Synaptopodin colocalizes with α-actinin-4 along actin filaments in differentiated cultured wild-type podocytes (magnification, ×650). (C) During kidney development, α-actinin-4 is already found in undifferentiated podocytes (arrows) of the S-shaped body stage (S) that have a cortical actin cytoskeleton. In contrast, synaptopodin is first found in the capillary loop stage (C) when podocytes start to develop long, unbranched contractile actin bundles (magnification, ×450). (D) Codistribution of synaptopodin with α-actinin-2 in the CA1, CA3, and dendate gyrus (DG) regions in the hippocampus of a 6-month-old wild-type mouse (magnification, ×650). (E) Lack of synaptopodin and downregulation of α-actinin-2 labeling in all regions of the hippocampus in an age-matched synpo–/– mouse (magnification, ×650). (F) Western blot analysis of cytosolic extract from glomeruli (left) and brains (right) of 6-month-old wild-type and synpo–/– mice. The levels of α-actinin-4 are not different between wild-type and synpo–/– mice. In contrast, there is a strong downregulation of α-actinin-2 in the brains of synpo–/– mice. Equal protein loading was confirmed by reprobing for tubulin.