Calcium mediated actin rearrangement (CAR) in podocyte development and pathogenesis
We have recently identified a fundamental property of mammalian cells to globally reset their actin cytoskeleton in response to calcium influx (Calcium mediated Actin Rearrangement - CAR). This reorganization is characterized by cortical actin disassembly and simultaneous actin assembly at the endoplasmic reticulum (ER). It is initiated within seconds and rapidly reverts within 1-3 minutes. As a consequence, the transcriptional co-activator MRTF-A is released from its inhibition by G-actin and activates a large number of SRF-dependent genes. In addition, we observe a persistent increase in lamellipodial activity during cell spreading and wound healing. One key regulator of CAR is the formin INF2. This unique regulator provides actin nucleation and severing activity in one protein and has been implicated in hereditary and acquired glomerular pathologies. In this proposal we intend to establish the molecular basis and physiological relevance of CAR for the development and pathophysiology of podocytes. These cells are essential for efficient ultrafiltration in the kidney. We will study CAR using cultured human podocytes, intact mouse glomeruli and fly nephrocytes as model systems.