A role for mRNA transport and local translation in podocytes
Understanding the mechanisms whereby mRNA transport and local translation maintain proper brain and kidney function is of great interest. Our studies focus on the role of the RNA binding protein Staufen 1 and Staufen 2 in locally regulating the actin cytoskeleton and cell adhesion. Both proteins associate with a specific subset of mRNAs and thereby regulate them post-transcriptionally.
We have gained data using immortalized podocytes demonstrating that Staufen 2 is involved in actin cytoskeleton dynamics and cell adhesion, both important features for maintaining the integrity of the glomerular filtration barrier. By co-precipitating Staufen 2-mRNA complexes from podocytes, followed by microarray analyses (RIP-Chip) we have now identified a group of Staufen 2 target mRNAs encoding cytoskeleton and adhesion regulators. In addition, we have developed conditional Staufen 2 knockout mice and show that they are more susceptible to kidney injury and develop proteinuria earlier than wild type mice. Disease is even more severe when both Staufen 1 and 2 are knocked out, suggesting functional redundancy in the kidney.
Recent studies have provided evidence for a role of Staufen 2 in synapse formation and spine morphogenesis. Moreover, it was shown that Staufen 2 knockdown resulted in premature differentiation of neural stem cells into neurons, demonstrating its functional importance for normal cortical development. These studies were performed using cultured cells and thus have their limitations. A second study demonstrated that cultured hippocampal neurons derived from Staufen 1 deficient mice show impaired dendritic spine morphogenesis. Despite this finding, no obvious behavioral deficit such as hippocampus dependent learning was observed. One of the reasons for the lack of a behavioral phenotype in Staufen 1 knockout mice may be functional redundancy between Staufen proteins, as seen in the kidney.
Given the role of Staufen proteins in neurons and the availability of our newly established Staufen KO mice we have started extending our studies to the brain. We first showed that Staufen 1 and 2 are co-expressed in the cortex, hippocampus and in Purkinje cells. In a series of behavioral experiments we could further demonstrate that deletion of Staufen 1 and 2 in mice affects learning, memory, anxiety, sociability and motor function, behaviors also affected in autism spectrum disorders (ASD). Interestingly, our RIP-Chip analysis on podocytes revealed a number of Staufen 2 target RNAs with known functions in ASD. As a next step we will investigate the molecular mechanisms whereby Staufen deletion in mice results in the observed ASD related behavior.