Development of the Metanephric Mesenchyme

Summary

Principal Investigator: S Potter
Abstract: The goal of this proposal is to define the overlapping functions of Hox genes in kidney development. The Hox genes encode transcription factors that often serve important roles in the genetic hierarchy of development. During the previous funding period we showed that 26 Hox genes are expressed during kidney development, with Hox genes flanking each other on a single cluster often showing strongly overlapping expression patterns. In addition, through a series of coding sequence exchange gene targeting experiments we showed that flanking Hox proteins are closely related functionally. These observations lead us to the hypothesis that flanking Hox genes, as well as paralogs, have a high level of redundancy during kidney development. To test this hypothesis we propose the creation of a series of mutant mice carrying strings of frameshift mutations in flanking Hox genes. We have devised a novel variant of recombineering that allows the rapid construction of BAG targeting vectors with multiple Hox mutations. A total of eleven targeting experiments will produce mice with overlapping sets of mutations in 17 Hox genes on three clusters. Interbreedings will make mice with compound arrays of flanking and paralogous Hox frameshift mutations. The resulting phenotypes will be analyzed by a combination of histology, immunohistochemistry, in situ hybridizations, and laser capture microdissection-microarray. This study would represent the first genetic dissection of the functional redundancy of both flanking and paralogous Hox genes in kidney development. Our hypothesis predicts synergistic severity of phenotype as additional flanking Hox genes are removed. In addition, the fine expression analysis of the resulting phenotypes, using laser capture and microarrays, will be capable of detecting even subtle shifts in gene expression patterns, defining overlapping sets of Hox target genes and effector pathways.
Funding Period: 2002-04-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts
    Anna M Raines
    Division of Developmental Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Development 140:2942-52. 2013
  2. pmc Microarrays and RNA-Seq identify molecular mechanisms driving the end of nephron production
    Eric W Brunskill
    Division of Nephrology and Hypertension, Cincinnati Children s Hospital Medical Center and the University of Cincinnati School of Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
    BMC Dev Biol 11:15. 2011
  3. ncbi Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice
    Eric W Brunskill
    Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
    Eur J Neurosci 22:1265-76. 2005
  4. ncbi Comprehensive microarray analysis of Hoxa11/Hoxd11 mutant kidney development
    Kristopher Schwab
    Division of Developmental Biology, Children s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
    Dev Biol 293:540-54. 2006
  5. pmc Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development
    Kristopher R Schwab
    Division of Developmental Biology, Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    BMC Biol 5:15. 2007
  6. ncbi Laser capture-microarray analysis of Lim1 mutant kidney development
    S Steven Potter
    Division of Developmental Biology, Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Genesis 45:432-9. 2007
  7. pmc Cessation of renal morphogenesis in mice
    Heather A Hartman
    Division of Nephrology and Hypertension, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Dev Biol 310:379-87. 2007
  8. pmc Epigenetic inheritance based evolution of antibiotic resistance in bacteria
    Mike Adam
    Division of Developmental Biology, Children s Hospital Research Foundation, 3333 Burnet Ave, Cincinnati, OH 45229, USA
    BMC Evol Biol 8:52. 2008

Scientific Experts

Detail Information

Publications8

  1. pmc Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts
    Anna M Raines
    Division of Developmental Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Development 140:2942-52. 2013
    ..These results identify novel molecular functions of Hox genes in the development of the male and female reproductive tracts. ..
  2. pmc Microarrays and RNA-Seq identify molecular mechanisms driving the end of nephron production
    Eric W Brunskill
    Division of Nephrology and Hypertension, Cincinnati Children s Hospital Medical Center and the University of Cincinnati School of Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
    BMC Dev Biol 11:15. 2011
    ..This strategy allowed us to define the changing gene expression states following induction and the onset of differentiation after birth...
  3. ncbi Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice
    Eric W Brunskill
    Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
    Eur J Neurosci 22:1265-76. 2005
    ..Together, our observations indicate an important role for Npas3 in controlling normal brain development and neurosignaling pathways...
  4. ncbi Comprehensive microarray analysis of Hoxa11/Hoxd11 mutant kidney development
    Kristopher Schwab
    Division of Developmental Biology, Children s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
    Dev Biol 293:540-54. 2006
    ..These results identify the multiple molecular pathways downstream of Hox11 function in the developing kidney...
  5. pmc Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development
    Kristopher R Schwab
    Division of Developmental Biology, Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    BMC Biol 5:15. 2007
    ..To better understand the functions of Pygopus-mediated canonical Wnt signaling in kidney development, targeted mutations were made in the two mammalian orthologs, Pygo1 and Pygo2...
  6. ncbi Laser capture-microarray analysis of Lim1 mutant kidney development
    S Steven Potter
    Division of Developmental Biology, Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Genesis 45:432-9. 2007
    ..This was confirmed by in situ hybridizations. It is interesting to note that Lim1 and Dkk1 mutant mice have striking similarities in phenoytpe. These results suggest that the Dkk1 gene might be a key downstream effector of Lim1 function...
  7. pmc Cessation of renal morphogenesis in mice
    Heather A Hartman
    Division of Nephrology and Hypertension, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Dev Biol 310:379-87. 2007
    ..These results suggest that the sequence of events leading to disruption of the cycle of branching morphogenesis and nephrogenesis began with the loss of mesenchyme that resulted from its conversion into nephrons...
  8. pmc Epigenetic inheritance based evolution of antibiotic resistance in bacteria
    Mike Adam
    Division of Developmental Biology, Children s Hospital Research Foundation, 3333 Burnet Ave, Cincinnati, OH 45229, USA
    BMC Evol Biol 8:52. 2008
    ..Evolution is the result of natural selection acting on variant phenotypes. Both the rigid base sequence of DNA and the more plastic expression patterns of the genes present define phenotype...