Integrated Project funded by the
European Community,
Framework Programme 6

coordinated by the
for Molecular Medicine (MDC)

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Topic 2 Renal Development

Workpackages (WP)
  • WP 2-1 Renal cell lines and cell lineage analysis
  • WP 2-2 Expression atlas of the developing and adult kidney
  • WP 2-3 Ureter induction, growth and branching
  • WP 2-4 Nephrogenesis
  • WP 2-5 Patterning and terminal differentiation
Coordinators: Andeas Schedl (2-1, 2-3, 2-4), André Brändli
Partners: Jamie Davies, Gregor Eichele, Nick Hastie, Matthias Kretzler, Steffan Ohlmeier, Seppo Vainio, Olivier Devuyst, Peirre Verroust, Thomas Willnow

Specific objectives in Renal development (Topic 2)

  • establish novel cell lines including murine stem cells for description of renal development programs
  • establish detailed maps of gene expression patterns of the developing and adult kidney
  • identify genes involved in nephrogenesis and in differentiation pathways from renal stem cells
Developmentally expressed genes will be identified on a large scale using microarray and in situ hybridization in cell lines, organ cultures and embryos, and their expression mapped back onto the developing kidney through novel imaging technologies. Functional studies will be performed using large scale knockdown (siRNA, morpholinos, insertion mutagenesis) and gain-of-function approaches in Xenopus and mouse, and in cell and organ cultures. Candidate genes will be followed up by gene targeting or transgenic studies. Cell lineage and organ culture studies will be performed to understand the origin of cellular components of the kidney. Differentiation pathways from renal stem cells to components of the kidney will be explored in the mouse.

WP 2-1 Renal cell lines and cell lineage analysis (Partners 1, 2a, 3a, 12, 16)

Specific objectives: Understanding the function of individual renal cell types requires careful analysis, which is best done in culture. While there are some renal cell lines available, they are either poorly charaterized or do not mimic the endogenous situation. Aim of this WP is to isolate cell lines of the developing kidney (including stem cells) and of thhe mature metanephros of the mouse.

Specific tasks:

  • Task 2-1-1 Isolation of renal cell lines
  • Task 2-1-2 Cell potency and lineage studies
WP 2-2 Expression atlas of the developing adult kidney (Partners 3a, 5, 6, 12, 16)

Specific objectives: The property of any cell type is primarily defined by its transcriptome. Consequently, it is important to analyze gene expression profiles of renal cell types to comprehend their function. While there is an increasing amount of isolated data on genes expressed during renal development and function, there is presently no systematic appropach to this problem. Thus WP 2-2 aims at establishing a map of genes expressed during renal development and in the adult kidney in mouse and Xenopus models. Besides establishing overall gene expression profiles, we will generate nephron segment-specific gene expression maps using manual and laser microdissection. In a complimentary approach, we will perform large scale in situ hybridization screens to identify genes encoding renal solute carriers (SLC gene famililes), homeobox transcription factors and G-protein-coupled receptors (GPCRs).

Specific tasks:

  • Task 2-2-1 Expression profiling during metanephric development
  • Task 2-2-2 Expression profiling of cell lines and nephron segments
  • Task 2-2-3 Expression profiling of specific gene families in mouse and Xenopus
WP 2-3 Ureter induction, growth and branchin (Partners 3a, 3c, 6, 12)

Specific objectives: The first step of metanephros developoment is the formation of the ureteric bud from the Wolffian duct. Signaling through the glial derived neurotrophic factor (GDNF) fulfils a key role in this process. After induction, the ureter invades the metanephric blastema, and is stimulated to further grow and branch. In WP 2-3 we aim to identify genes underlying ureter development and characterize their significance using organ cultures and mouse models.

Specific tasks:

  • Task 2-3-1 Identification of new genes involved in ureter induction
  • Task 2-3-2 Mechanism of ureter branching
  • Task 2-3-3 vHnf1 in renal development
  • Task 3-3-4 Functional analysis of novel candidate genes
WP 2-4 Nephrogenesis (Partners 2a, 3a, 6, 12)

Specific obectives: Nephrogenesis occurs as a result of interactions between the tip of the ureter and the metanephric blastema. The blastema condenses and undergoes a complex series of morphogenetic events giving rise to the nephron with its specific components. Objective is the identification of genes and molecular mechanisms involved in nephron formation.

Specific tasks:

  • Task 2-4-1 Inducing nephrogenesis: signals from the ureter
  • Task 2-4-2 Inducing nephrogenesis: the forle of Wt1 and Wnt4
  • Task 2-4-3 formation of a polarized epithelium
WP 2-5 Patterning and terminal differentiation (Partners 3a, 3b, 6, 12, 16)

Specific objectives: The final step of renal development is the terminal differentiation of precursor cells into disticnt renal cell types, which gives rise to the patterened expression along the nephron. Functional analysis over the last years allowed the identification of a number of genes involved in this process. however, it is clear that a vast number of genes remain to be identified as well as the molecular events leading to a patterned nephron. WP 2-5 aims for a large-scale approach to identify such regulators responsible for the differentiation of stem cells into renal specific subtypes. Finally, we will establish a co-culture system to reconstitute in vitro the glomerular filtration apparatus, which can be exploited for sophisticated functional analysis.

Specific tasks:

  • Task 2-5-1 Terminal differentiation of renal cells
  • Task 2-5-2 Analysis of homeobox transcription factors
  • Task 2-5-3 Tissue engineering
  last update 23.04.2008, by Chris Tindal