Developmental Cellular Physiology and Pathophysiology Lab

  • Function of the Wilms tumor protein WT1 in embryonic development and disease
  • Molecular mechanisms of oxygen-dependent gene expression
  • Developmental erythropoietin production in liver and kidney
  • Role of polyamines in acute and chronic kidney injury

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  • Developmental Cellular Physiology and Pathophysiology Lab.

Main research topics of the Developmental Cellular Physiology and Pathophysiology Lab

Our group is interested in transcriptional mechanisms controlling cardiovascular development and formation of the genitourinary system. The major focus of our work is on the regulation and function of the Wilms’ tumor gene, WT1. Another research topic is the regulation of gene expression by the local oxygen concentration and hypoxia, respectively.

Research Topic

Immunohistochemical staining of the Wilms tumor protein WT1 in murine embryonic kidney. WT1 is present in cells that give rise to the future podococytes of the glomeruli (arrows). Courtesy of Dr. Karin Kirschner
Immunohistochemical staining of the Wilms tumor protein WT1 in murine embryonic kidney. WT1 is present in cells that give rise to the future podococytes of the glomeruli (arrows). Courtesy of Dr. Karin Kirschner

Our group is interested in transcriptional mechanisms controlling cardiovascular development and formation of the genitourinary system. The major focus of our work is on the regulation and function of the Wilms' tumor gene, WT1. Another research topic is the regulation of gene expression by the local oxygen concentration and hypoxia, respectively.

Based on its mutational inactivation in pediatric renal malignancies (Wilms' tumor, nephroblastoma) WT1 has been identified as a tumor suppressor gene. The WT1 gene product belongs to a group of zinc finger proteins that regulate gene transcription by binding to a GC-rich consensus sequence. Some WT1 splice variants exhibit a reduced DNA binding affinity and have been implicated in mRNA processing. Targeted inactivation of Wt1 in mice caused a failure of normal formation of the kidneys and gonads, the mesothelium, hematopoietic tissue and sensory neuroepithelia. Wt1-deficient murine embryos die from a failure of normal heart formation, which is likely due to impaired vascularization of the developing myocardium. Accumulating evidence suggests a role of WT1 in the epithelial-to-mesenchymal transition (EMT) of epicardial progenitor cells, which possess the characteristics of cardiac stem cells. WT1 expression in the heart is increased in hypoxia.

By studying the regulation of WT1 and by identifying WT1 downstream target genes we aim at deciphering key molecular events in cardiovascular and genitourinary differentiation. Our recent findings indicate that WT1 stimulates transcription of the metalloproteinase ADAMTS16 in murine embryonic kidneys and gonads. Transcriptional activation of the Adamts16 gene by WT1 is a critical mechanism for the normal development of these tissues.

Our research is driven by a genuine interest in the transcriptional signaling mechanisms underlying normal embryogenesis. Importantly, the adult organism frequently reactivates an embryonic gene expression program in response to tissue damage. Reexpression of "fetal genes", including WT1, is likely to promote and sustain organ repair. A detailed knowledge of the key molecular pathways in embryonic development can therefore provide important insights in regenerative processes following tissue injury.

Funding

German Research Foundation: DFG KI 1441/4-1: Molecular mechanisms of adaptation to intrauterine and perinatal changes of oxygen partial pressure: The liver-to-kidney switch of Erythropoietin production as model System, 2017-2020.

Else Kröner-Fresenius-Stiftung: 2014_A23: The Wilms tumor protein Wt1 and diabetes mellitus, 2014-2017

German Research Foundation: DFG SCHO 634/8-1: Regulation and synergism of transcription factors Wt1 and Gata 4 in the heart and gonads, 2011-2014.

German Research Foundation: DFG SCHO 634/6-1: Mechanisms and consequences of an oxygen-dependent expression of TrkB neurotrophin receptor, 2007-2010.

German Research Foundation: DFG FA 845/2-2: Posttranscriptional control of bHLH transcription factor Mash1 gene expression rate, in co-operation with Prof. Dr. Michael Fähling, 2008-2014.

German Research Foundation: DFG DA 484/2-1: Regulation of the erythropoietin and its receptor gene by the Wilmstumor transcription factor Wt1: Significance for hematopoieses, in co-operation with Prof. Dr. Christof Dame, 2005-2007.

German Research Foundation: DFG SCHO 634/5-1: Wt1 expression in the myocardial vasculature: Mechanisms and consequences, 2003-2006.

German Research Foundation: DFG SCHO 634/4-1: Identification of downstream target genes of the Wilmstumor transcription factor Wt1, 2002-2005.

BMBF NGFN-KGCV1-01GS0416, National Genome Research Network II, in co-operation with PD Dr. B. Nafz

Collaboration

  • Prof. Dr. Christof Dame (Klinik für Pädiatrie m. S. Molekulare Neonatologie, Charité, Berlin)
  • Prof. Dr. Christoph Englert (Fritz Lipmann-Institut, Jena)
  • Prof. Dr. Christian Freund (Institut für Biochemie, Freie Universität Berlin)
  • Prof. Dr. Andreas Schedl (INSERM U145, Nizza, Frankreich)
  • PD Dr. Kay-Dietrich Wagner (INSERM U907, Nizza, Frankreich)

Publications (since 2006)

Müller M, Bondke Persson A, Krueger K, Kirschner KM, Scholz H: The Wilms tumor protein WT1 stimulates transcription of the gene encoding insulin-like growth factor binding protein 5 (IGFBP5). Gene 619: 21-29, 2017

Rudigier LJ, Dame C, Scholz H, Kirschner KM: Ex vivo cultures combined with vivo-morpholino induced gene knockdown provide a system to assess the role of WT1 and GATA4 during gonad Differentiation. PLOS one 12: e0176296, 2017

Kasim, M, Heß V, Scholz H, Persson PB, Fähling M: Achaete-Scute Homolog 1 Expression Controls Cellular Differentiation of Neuroblastoma. Frontiers in Molecular Neuroscience 9:156, 2016

Krueger K, Shen J, Maier A, Tepel M, Scholze A: Lower Superoxide dismutase 2 (SOD2) Protein Content in mononuclear cells is associated with better survival in patients with hemodialysis therapy. Oxidative Medicine and Cellular Longevity, Volume 2016. Article ID 7423249, 8 pages, 2016

Holzweber M, Lippitz A, Krueger K, Jankowski J, Unger WES: Surface characterization of dialyzer polymer membranes by Imaging ToF-SIMS and quantitative XPS line scans. Biointerphases 10: 019011, 2015

Persson PB, Müller M: Transcription. Acta Physiologica 215: 159-160, 2015

Schley G, Scholz H, Kraus A, Hackenbeck T, Klanke B, Willam C, Wiesener MS, Heinze E, Burzlaff N, Eckardt K-U, Buchholz B: Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis. Kidney Intern., 88: 1283-1292, 2015

Albert GI, Schell C, Kirschner KM, Schäfer S, Naumann R, Müller A, Kretz O, Kuropka B, Girbig M, Hübner N, Krause E, Scholz H, Huber TB, Knobeloch K-P, Freund C: The GYF Domain Protein CD2BP2 is critical for embryogenesis and podocyte function. J Mol Cell Biol, 7: 402-414, 2015

Staudacher JJ, Naarmann-de Vries IS, Ujvari SJ, Klinger B, Kasim M, Benko E, Ostareck-Lederer A, Ostareck DH, Bondke Persson A, Lorenzen S, Meier JC, Blüthgen N, Persson PB, Henrion-Caude A, Mrowka R, Fähling M: Hypoxia-induced gene expression results from selective mRNA partitioning to the endoplasmic reticulum. Nucleic Acids Research, 43: 3219-3236, 2015

Kirschner KM, Braun JFW; Jacobi CL, Rudigier LJ, Bondke Persson A, Scholz H: Amine Oxidase Copper-containing 1 (AOC1) Is a Downstream Target Gene of the Wilms Tumor Protein, WT1, during Kidney Development. Journal of Biological Chemistry 289: 24452-24462, 2014

Jacobi CLJ, Rudigier LJ, Scholz H, Kirschner KM: Transcriptional regulation by the Wilms tumor protein, Wt1, suggests a role of the metalloproteinase Adamts16 in murine genitourinary development. Journal of Biological Chemistry 289(16): 11566, 2014 (Additions and Corrections)Dülsner A, Gatzke N, Hillmeister P, Glaser J, Zietzer A, Nagorka S, Janke D, Pfitzner J, Stawowy P, Meyborg H, Urban D, Bondke Persson A, Buschmann IR: PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain. Acta Physiologica, 210: 354-368, 2014

Bondke Persson A and Persson PB: Sleep. Acta Physiologica 210: 229-230, 2014

Bondke Persson A and Persson PB: Dealing with radicals. Acta Physiologica 210: 2-4, 2014

Bondke Persson, A and Persson, PB: The physiologist: researcher, inventor, physician, educator and visionary. Acta Physiologica 209: 193-194, 2013

Bondke Persson A: G – protein – receptors, signals and function. Acta Physiol 209: 91-93, 2013

Bondke Persson A, Persson PB: Tools of our trade. Acta Physiol 208: 289-291, 2013

Bondke Persson A, Persson PB: On beauty. Acta Physiol 208: 215- 217, 2013

Duelsner A, Bondke Persson A: Animal models in cardiovascular research. Acta Physiol 208: 1- 5, 2013

Persson PB, Bondke Persson A: Nitric oxide: a classic revisited. Acta Physiologica 207: 427-429, 2013

Persson PB, Bondke Persson A: A matter of taste. Acta Physiologica 207: 203-205, 2013

Persson PB, Bondke Persson A: Obesity: The BIG issue. Acta Physiologica 207: 1-4, 2013

Jacobi CLJ, Rudigier LJ, Scholz H, Kirschner KM: Transcriptional regulation by the wilms tumor protein, Wt1, suggests a role of the metalloproteinase Adamts16 in murine genitourinary development. The Journal of Biol Chem 288(26): 18811-18824, 2013

Fähling M, Persson AB, Klinger B, Benko E, Steege A, Kasim M, Patzak A, Persson PB, Wolf G, Blüthgen N, Mrowka R: Multi-level regulation of HIF-1 signaling by TTP. Mol Biol Cell 23:4129-4141, 2012

Bondke Persson A and Persson, PB: Cycling in Physiology. Acta Physiologica (Oxford) 206: 1-3, 2012

Dülsner A, Gatzke N, Glasner J, Hillmeister P, Li M, Lee EJ, Lehmann K, Urban D, Meyborg H, Stawowy P, Busjahn A, Nagorka S, Bondke Persson A, Buschmann IR: Acetylsalicylic acid, but no clopidogrel, inhibits therapeutically induced cerebral arteriogenesis in the hypoperfused rat brain. J Cerebral Blood Flow & Metabolism 32: 105-114, 2012

Dülsner A, Gatzke N, Glaser J, Hillmeister P, Li M, Lee EJ, Lehmann K, Urban D, Meyborg H, Stawowy P, Busjahn A, Nagorka S, Bondke Persson A, Buschmann IR: Granulocyte Colony-Stimulating Factor Improves Cerebrovascular Reserve Capacity by Enhancing Collateral Growth in the Circle of Willis. Cerebrovascular Diseases 33: 419-429, 2012

Persson PB, Bondke Persson A: Age your garlic for longevity. Acta Physiologica (Oxford) 205: 1-2, 2012

Bondke Persson A and Persson PB: Let 'em grow: the Yin and Yang of vessel growth. Acta Physiologica (Oxford) 204: 466-468, 2012

Bondke Persson A and Persson, PB: Getting a kick out of thermoregulation. Acta Physiologica (Oxford) 204: 291-293, 2012

Bondke Persson A, Buschmann E-E, Lindhorst R, Troidl K, Langhoff R, Schulte K-L, Buschmann I: Therapeutic arteriogenesis in peripheral arterial disease: combining intervention and passive training. Vasa 40:177-187, 2011

Scholz H, Kirschner KM: Oxygen-dependent gene expression in development and cancer: lessons learned from the Wilms' tumor gene, WT1. Front Mol Neurosci. 4, Article 4:1-11, 2011

Bondke Persson A, Buschmann IR: Vascular growth in health and disease. Frontiers in Molecular Neuroscience 4, 2011

Benko E, Winkelmann A, Meier JC, Persson PB, Scholz H, and Fähling M: Phorbol-ester mediated suppression of hASH1 synthesis: Multiple ways to keep the level down. Front Mol Neurosci. 4, Article 1:1-11, 2011

Sciesielski LK, Kirschner KM, Scholz H, Persson AB. Wilms' tumor protein Wt1 regulates the Interleukin-10 (IL-10) gene. FEBS Letters 584:4665-4671, 2010.

Kirschner KM, Sciesielski LK, Scholz H. Wilms' tumor protein Wt1 stimulates transcription of the gene encoding vascular endothelial cadherin. Pflügers Arch.-Europ. J. Physiol. 460:1051-1061, 2010.

Sciesielski LK, Paliege A, Martinka P, Scholz H. Enhanced pulmonary expression of the TrkB neurotrophin receptor in hypoxic rats is associated with increased acetylcholine-induced airway contractility. Acta Physiol. 197:253-264, 2009.

Fähling M, Mrowka R, Steege A, Kirschner KM, Benko E, Förstera B, Persson PB, Thiele BJ, Meier JC, Scholz H. Translational regulation of the human achaete-scute homologue-1 by fragile X mental retardation protein. J. Biol. Chem. 284(7):4255-4266, 2009.

Scholz H, Wagner KD, Wagner N. Role of the Wilms' tumor transcription factor, Wt1, in blood vessel formation. Pflügers Arch.-Europ. J. Physiol. 458:315-323, 2009.

Kirschner KM, Hagen P, Hussels CS, Ballmaier M, Scholz H, Dame C: The Wilms' tumor suppressor Wt1 activates transcription of the erythropoietin receptor in hematopoietic progenitor cells. FASEB J. 22(8):2690-2701, 2008.

Steege A, Fähling M, Paliege A, Bondke A, Kirschner KM, Martinka P, Kaps C, Patzak A, Persson PB, Thiele BJ, Scholz H, Mrowka R. Wilms' tumor protein WT1(-KTS) modulates renin gene transcription. Kidney Int. 74(4):458-466, 2008.

Martens LK, Kirschner KM, Warnecke C, Scholz H: Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of the TrkB neurotrophin receptor gene. J.Biol.Chem. 282(19):14379-14388, 2007.

Kirschner KM, Wagner N, Wagner KD, Wellmann S, Scholz H: The Wilms tumor suppressor Wt1 promotes cell adhesion through transcriptional activation of the alpha4integrin gene. J.Biol.Chem. 281(42):31930-31939, 2006.

Wagner N, Wagner KD, Scholz H, Kirschner KM, Schedl A: Intermediate filament protein nestin is expressed in developing kidney and heart and might be regulated by the Wilms' tumor suppressor Wt1. Am.J.Physiol.Regul.Integr.Comp.Physiol. 291(3):R779-787, 2006.

Dame C, Kirschner KM, Bartz KV, Wallach T, Hussels CS, Scholz H: Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. Blood 107 (11):4282-4290, 2006.