Hippo signaling and hereditary kidney diseases

The Hippo signaling pathway has been identified as a central regulator of essential processes such as organ and cell proliferation, cell migration, and apoptosis. It represents an evolutionarily conserved signaling network consisting of a kinase cascade resulting in the phosphorylation of the downstream effectors YAP and TAZ. During the last decade, Hippo Signaling turned out to be an essential regulator in kidney biology and disease. Initially, we contributed to this concept and described dysregulation in Hippo Signaling in pediatric cystic kidney diseases.

Our goal is to better understand the molecular mechanisms underlying pediatric genetic kidney diseases. Therefore, we are part of a network of pediatric nephrologists, nephrologists, pathologists, human geneticists, and biologists that boosters transfer of important knowledge and ideas both from bench to bedside as well as from bedside to bench. This translational approach enables us to identify novel disease-causing mutations in rare diseases and - simultaneously- decipher the molecular mechanisms related to the mutation in patient-derived cells.

Our recent work focuses on the role of the transcriptional regulators YAP and TAZ in podocyte disease. In our translational approach, we demonstrated that TAZ and YAP are indeed dysregulated in a cells derived from patients with a very recently identified podocyte disorder caused by mutations in the protocadherin FAT1. To transfer data from rare genetic diseases to a more general understanding of podocyte biology, we complement our work with mouse models harboring specific genetic modifications in Hippo Signaling. The finding that both, knockout and transgenic expression of YAP in podocytes, results in podocyte damage further supports our hypothesis of a very narrow control of Hippo Signaling to be crucial for podocyte integrity.