Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner.
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 alpha-actinin and elongate alpha-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 alpha-actinin in highly dynamic cell compartments, such as podocyte FPs and the dendritic spine apparatus.
Asanuma
Katsuhiko
K
Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA.
Kim
Kwanghee
K
Oh
Jun
J
Giardino
Laura
L
Chabanis
Sophie
S
Faul
Christian
C
Reiser
Jochen
J
Mundel
Peter
P
D000185:Actinin / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008854:Microscopy, Electron; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000199:Actins; D008840:Microfilament Proteins; D020033:Protein Isoforms; C503968:Synpo protein, mouse; D000185:Actinin