Scope
Kidney development and kidney disease
In the mammalian embryo, formation of the definitive kidney is initiated during mid-embryogenesis, when the ureteric bud, an epithelial tubule extending from the posterior Wolffian duct, interacts with an adjacent progenitor cell population, the metanephric mesenchyme. The Wolffian duct undergoes branching morphogenesis to give rise to the ureter, renal pelvis and collecting duct system, while the metanephric mesenchyme converts into epithelial cells that subsequently get patterned along the proximal-distal axis to form the different cell types of the nephron. As these cells differentiate, they obtain epithelial characteristics, including the establishment of apico-basal polarity and the formation of epithelial-specific junctions. Our laboratory investigates the molecular mechanisms underlying these events, which are intriguing for several reasons. First, mammalian embryonic kidney development constitutes a classical model system in developmental biology, in which branching morphogenesis and tubulogenesis occur in parallel. The sequence of events can be closely monitored in organ cultures, in which key in vivo aspects of nephrogenesis are recapitulated. Exogenous or genetic perturbations of kidney development result in congenital kidney diseases. Furthermore, adult kidney epithelia preserve the ability to reactivate molecular pathways from earlier developmental stages in certain disease states, including tumors, kidney fibrosis, and acute tubular injury.
Sites of TCF/Lef activity in the developing kidney (K) and
adjacent adrenal gland (A).
(Image property of K. M. Schmidt-Ott and J. Barasch)
Wnt signaling in kidney development and disease
Wnt proteins are a family of secreted molecules that are 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 epithelial differentiation in metanephric mesenchymal progenitor cells. In addition, this pathway provides proliferative and antiapoptotic signals that regulate the size of the progenitor pool. As part of a DFG funded project (Schm 1730/2-1) we characterize the target gene program of TCF/Lef signaling in the kidney. One crucial aspect of our studies is to elucidate the role of Wnt signaling in kidney disease, with an emphasis on the canonical TCF/Lef-dependent pathway. For this purpose we are using different genetic and experimental mouse models, which we analyze using genome-wide analysis of expression and transcription factor binding. We believe that a detailed elucidation of the transcriptional network controlled by TCF/Lef will yield fundamental insights into growth, remodeling, and regeneration in the kidney.
Polarized collecting duct epithelial cells in culture
(Image property of M. Werth and K. M. Schmidt-Ott)
Transcriptional control of epithelial differentiation
While TCF/Lef-dependent signaling may account for early developmental programs in renal epithelial progenitors, it may in fact be inhibitory to terminal differentiation of tubular epithelia. Therefore, we are seeking complementary transcriptional regulators that induce the establishment of epithelial polarity and the expression of segment-specific markers. We recently identified Grhl2, a novel transcriptional regulator of aspects of terminal differentiation, which belongs to the grainy head family of transcription factors. Characterization of Grhl2 is part of a DFG-funded project (Schm 1730/3-1) within FG “Epithelial mechanisms of renal volume regulation”(FOR667).
Mechanisms of renal tubular injury and repair
Re-expression of embryonic marker molecules is a common feature in disease states and is believed to participate in compensation and regeneration. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein in the developing kidney that is sufficient to induce differentiation in embryonic renal epithelial progenitors. NGAL is also markedly reactivated in tubular injury of the kidney and its urinary excretion is closely correlated with the temporal onset and severity of tubular injury. In collaboration with Jonathan Barasch (Columbia University, New York), Friedrich C. Luft (ECRC) and Ralph Kettritz (ECRC), we are conducting clinical studies to test the performance of NGAL as a urinary and plasma biomarker of acute kidney injury. We are aiming to optimize diagnostic algorithms that utilize NGAL measurements to predict renal injury or to differentiate renal injury from related clinical entities. This project serves as a prime example to illustrate the importance of an understanding of basic molecular mechanisms in the embryo to address the diagnosis of renal disease in the adult. Translational aspects of our research are markedly enhanced by our close ties to the ‘Experimental and Clinical Research Center’ (ECRC), which serves as a bridge between basic and clinical research at the MDC.