Research Report 2010 - MDC

Structure of the GroupKai M. Schmidt-Ott(Emmy NoetherResearch Group)Group LeaderProf. Dr. Kai M. Schmidt-OttScientistsDr. Max WerthGraduate StudentsAnnekatrin AueAntje ElgerEugenia SingerKatharina WalentinAnne-Katharina WübkenTechnical AssistantsTatjana LuganskajaAntje SommerManager of SponsoredProgramsSusanne WisslerDevelopmental Biology andPathophysiology of the KidneyThe kidney is a central organ in cardiovascular diseases. It excretes toxins into the urine,regulates volume and solute homeostasis in the body, and produces hormones. The kidney isnot only itself a target in cardiovascular disease and but also is centrally involved in cardiovascularhomeostasis. Moreover, kidney failure constitutes one of the most important risk factors for othercardiovascular diseases. The kidney is composed of structural units called nephrons, which consistof several different types of renal epithelial cells that facilitate directional transport. Our groupstudies the molecular mechanisms of nephron morphogenesis and the maintenance of epithelialintegrity later in life. We focus on transcription factors and their regulation of aspects of epithelialdifferentiation. We use mouse models and epithelial cell culture systems and employ a widespectrum of techniques, including genome-wide gene expression analysis, DNA-protein inter -action analysis as well as organ culture techniques of the developing kidney.Kidney DevelopmentIn the mammalian embryo, formation of the definitivekidney is initiated during mid-embryogenesis, when theureteric bud, an epithelial tubule extending from theposterior Wolffian duct, interacts with an adjacent progenitorcell population, the metanephric mesenchyme.The ureteric bud undergoes branching morphogenesisto give rise to the ureter, renal pelvis and collecting ductsystem, while the metanephric mesenchyme convertsinto epithelial cells that subsequently get patternedalong the proximal-distal axis to form the different celltypes of the nephron. As these cells differentiate, theyobtain epithelial characteristics, including the establishmentof apico-basal polarity and the formation ofepithelial-specific junctions. Our laboratory investigatesthe molecular mechanisms underlying theseevents, which are intriguing for several reasons.First, mammalian embryonic kidney development constitutesa classical model system in developmental biology,in which branching morphogenesis and tubulogenesisoccur in parallel. The sequence of events can beclosely monitored in organ cultures, in which key in vivoaspects of nephrogenesis are recapitulated. Exogenousor genetic perturbations of kidney development resultin congenital kidney diseases. Furthermore, adult kidneyepithelia preserve the ability to reactivate molecularpathways from earlier developmental stages in certaindisease states, including tumors, kidney fibrosis,and acute tubular injury.Wnt signaling in Kidney Development andDiseaseWnt proteins are a family of secreted molecules thatare important for various aspect of embryonic development.Several WNT molecules, including Wnt4, Wnt7b,and Wnt9b, are centrally involved in kidney development.We previously found that Wnt signaling via the β-catenin/TCF/Lef pathway mediates aspects of epithelialdifferentiation in metanephric mesenchymal progenitorcells. In addition, this pathway provides proliferativeand antiapoptotic signals that regulate the size of theprogenitor pool. As part of a DFG funded project (Schm1730/2-1) we characterize the target gene program of24 Cardiovascular and Metabolic Disease Research