Genetic Control of Ureter and Kidney Development

Summary

Principal Investigator: FRANKLIN D COSTANTINI
Affiliation: Columbia University
Country: USA
Abstract: Little is known about the developmental mechanisms that determine the size of the kidney and the number of nephrons. Why does the kidney grow to a particular size and complexity, and then stop? Is there an intrinsic limitation in the number of divisions of progenitor cells, or is organ size regulated by some other mechanism, such as external signals? In this Revision application, we propose new experiments to address these questions. Two major renal cell lineages are the collecting duct epithelia, which derive from the ureteric bud, and the nephron epithelia, which derive from the metanephric mesenchyme. Cells expressing the Ret receptor, located at the tips of the ureteric bud, are the major progenitors of collecting ducts, while metanephric mesenchyme cells expressing the Ret- ligand GDNF are the progenitors of nephron epithelia. We will use mice expressing an inducible form of Cre recombinase (Cre-ERT2) under the control of the Ret or Gdnf genes. These mice will be crossed with a strain that conditionally expresses a cytotoxic gene, DTA, only in cells that express active Cre, and in their descendants. By inducing Cre activity with Tamoxifen, we will selectively reduce the number of the progenitor cells in the ureteric bud or metanephric mesenchyme, at specific stages of kidney development. We will then analyze the kidneys in vivo and in organ culture, to ask if this alters the rates of ureteric bud growth and nephrogenesis, and the final kidney size and nephron number. If the progen- itors are programmed to divide a limited number of times, then destroying a fraction of them should result in decreased organ size. Alternatively, if these cells have excess proliferative capacity and are regulated by external signals, the organ may recover and reach its normal size. Either the number of ureteric bud or nephron progenitor cells, or both, might limit the growth rate and final size of the kidney. Our experiments also address the basic question of whether tip cell number might determine the rates of elongation and branching of the ureteric bud, and similarly, how the number of nephron progenitors might affect the rate of formation and the size of nephrons. Understanding how the kidney achieves its normal size and nephron number has very important clinical implications, as reduced nephron number may favor the progression of renal diseases and hypertension. The proposed studies expand the scope of our original project (whose Aims concern the regulation of kidney development by growth factors, tyrosine kinase receptors, and intracellular signaling mechanisms) to include studies on the role of progenitor cells in kidney growth and development. It will allow for job creation by providing the funds to hire new postdoctoral researchers, and to purchase additional supplies and services. PUBLIC HEALTH RELEVANCE: Understanding how the kidney achieves its normal size has important clinical implications, as defects in organ growth during fetal development can lead to a reduction in the number of nephrons, the filtering units. This, in turn, may promote the progression of renal diseases and hypertension. This proposal investigates the mechanisms that control how the kidney grows to the correct size, and how the proper number of nephrons is formed.
Funding Period: 2009-09-25 - 2011-09-24
more information: NIH RePORT

Top Publications

  1. pmc Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system
    Frank Costantini
    Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
    Wiley Interdiscip Rev Dev Biol 1:693-713. 2012
  2. pmc Mitogen-activated protein kinase (MAPK) pathway regulates branching by remodeling epithelial cell adhesion
    Anneliis Ihermann-Hella
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    PLoS Genet 10:e1004193. 2014
  3. pmc The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment
    Cristina Cebrian
    Department of Genetics and Development, Columbia University, New York, NY 10032, USA
    Cell Rep 7:127-37. 2014
  4. pmc Kidney development: from ureteric bud formation to branching morphogenesis
    Odysse Michos
    Department of Genetics and Development, Columbia University Medical Center, HHSC1416, New York, NY 10032, USA
    Curr Opin Genet Dev 19:484-90. 2009
  5. pmc Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development
    Frank Costantini
    Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA
    Dev Cell 18:698-712. 2010
  6. pmc GDNF/Ret signaling and renal branching morphogenesis: From mesenchymal signals to epithelial cell behaviors
    Frank Costantini
    Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
    Organogenesis 6:252-62. 2010
  7. pmc Kidney development in the absence of Gdnf and Spry1 requires Fgf10
    Odysse Michos
    Department of Genetics and Development, Columbia University, New York, New York, USA
    PLoS Genet 6:e1000809. 2010

Scientific Experts

  • FRANKLIN D COSTANTINI
  • Odysse Michos
  • Anneliis Ihermann-Hella
  • Cristina Cebrian
  • Naoya Asai
  • Maria Lume
  • VIVETTE D'AGATI
  • Mart Saarma
  • Satu Kuure
  • Anniina Pirttiniemi
  • Ilkka J Miinalainen
  • Yujuan Gui
  • Johan Peranen
  • Jean Charron

Detail Information

Publications7

  1. pmc Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system
    Frank Costantini
    Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
    Wiley Interdiscip Rev Dev Biol 1:693-713. 2012
    ..In addition, our current knowledge of cellular behaviors that are controlled by these genes and underlie development of the collecting system is reviewed...
  2. pmc Mitogen-activated protein kinase (MAPK) pathway regulates branching by remodeling epithelial cell adhesion
    Anneliis Ihermann-Hella
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    PLoS Genet 10:e1004193. 2014
    ..We show that MAPK activity is required for branching morphogenesis, and propose that it promotes cell cycle progression and higher cellular motility through remodeling of cellular adhesions. ..
  3. pmc The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment
    Cristina Cebrian
    Department of Genetics and Development, Columbia University, New York, NY 10032, USA
    Cell Rep 7:127-37. 2014
    ..However, the retarded UB branching impaired kidney growth, leaving a permanent nephron deficit. Thus, the number of fetal nephron progenitor cells is an important determinant of nephron endowment, largely via its effect on UB branching. ..
  4. pmc Kidney development: from ureteric bud formation to branching morphogenesis
    Odysse Michos
    Department of Genetics and Development, Columbia University Medical Center, HHSC1416, New York, NY 10032, USA
    Curr Opin Genet Dev 19:484-90. 2009
    ..The invasion of the metanephric mesenchyme by the UB is a fundamental step toward establishing the cyto-architecture of the kidney and determining the number of nephrons, which form the filtration units of the adult kidney...
  5. pmc Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development
    Frank Costantini
    Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA
    Dev Cell 18:698-712. 2010
    ..In this review, we will consider their embryological origin and the genes controlling their morphogenesis, patterning, and differentiation, with a focus on recent advances in several areas...
  6. pmc GDNF/Ret signaling and renal branching morphogenesis: From mesenchymal signals to epithelial cell behaviors
    Frank Costantini
    Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
    Organogenesis 6:252-62. 2010
    ..Ret signaling, via Etv4 and Etv5, promotes competitive cell rearrangements in the nephric duct, in which the cells with the highest level of Ret signaling preferentially migrate to form the first ureteric bud tip...
  7. pmc Kidney development in the absence of Gdnf and Spry1 requires Fgf10
    Odysse Michos
    Department of Genetics and Development, Columbia University, New York, New York, USA
    PLoS Genet 6:e1000809. 2010
    ..In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals...