Molecular programs controlling development and tissue homeostasis

Development and tissue maintenance are highly interrelated processes and molecular programs driving development and differentiation are also triggered when stem cells become activated to replace damaged or lost cells. In our research program we try to understand the transcriptional control underlying tissue development, define stem/progenitor cells in the adult organism and determine the signaling pathways involved in their maintenance and activation. As a model of choice we use the mouse, as its physiology largely reflects that of the human body and as it allows easy manipulation of its genome using transgenic and gene-targeting techniques.


Fig1.: E18.5 developing kidney stained with antibodies WT1 (blue), Pax2 (green) and DBA (red). BN) E18.5 kidney stained with antibodies against WT1 (red) and nephrin (green), a marker for glomerular podocytes.

The mammalian kidney: a paradigm for complex organ development

Kidney function is vital for the human body. It is not only required for the excretion of waste compounds, but also a central cardiovascular organ and as such involved in controlling blood pressure, bone density, electrolyte, mineral, and acid-base balance. Given this multitude of functions it is not surprising that kidney diseases belong to the most common causes of morbidity in developed countries and affect approximately 1 out of 10 adults.

Kidney development requires the tight control of proliferation, apoptosis, cellular movements and differentiation. This control is coordinated by hundreds of transcription factors that form complex networks of interaction. We employ a combination of biochemical (e.g. ChIP-Seq) and genetic techniques to dissect the function of transcriptional regulators in renal development and determine the transcriptional programs regulated by them. Several of our genetically modified mice also represent excellent models for human disease and we are using them to understand the molecular events occurring in these pathologies. Indeed, our research has identified a set of novel candidate genes that we are presently analysing for their involvement in human disease.

 


Fig3.: Cell lineage tracing experiments identify a novel stem/progenitor
cell population in adult adrenals.

Tissue homeostasis and repair

Tissue repair in most organs is guaranteed through resident stem/progenitor cells. While stem cells are essential for organ renewal, there exists clear evidence for an involvement in disease: Lack of activation or depletion of the stem cell pool can lead to progressive organ failure, whereas overactivation of stem cells and their transiently proliferating derivatives can cause overgrowth and cancer.

A second focus of our group is therefore to address some of the key questions in stem cell biology: What is the differentiation capacity of resident stem/progenitor cells? Which factors determine their identity and which signaling pathways control their maintenance and activation? What is the time course of activation during repair processes? Finally, what are the links between stem cells and cancer? To achieve these goals we use genetic analysis in mice including reporter strains to monitor the activity of signaling pathways, cell lineage tracing to allow fate mapping, and inducible knockout and knockin mice to specifically manipulate gene expression in the adult organism.


Fig 4.: Overactivation of signaling pathway predispose to adrenal cancer.

 

Last publications

Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney. - 2015 - Cell reports - 12 P1325-38 - Kumar S, Liu J, Pang P, Krautzberger AM, Reginensi A, Akiyama H, Schedl A, Humphreys BD, and McMahon,AP

Alternatively spliced isoforms of WT1 control podocyte-specific gene expression. - 2015 - Kidney international - 88 P321-31 - Lefebvre J, Clarkson M, Massa F, Bradford ST, Charlet A, Buske F, Lacas-Gervais S, Schulz H, Gimpel C, Hata Y, Schaefer F, and Schedl,A

Steroidogenic organ development and homeostasis: A WT1-centric view. - 2015 - Molecular and cellular endocrinology - 408 P145-55 - Bandiera R, Sacco S, Vidal VP, Chaboissier MC, and Schedl,A

WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors. - 2014 - Nature communications - 5 P4444 - Motamedi FJ, Badro DA, Clarkson M, Lecca MR, Bradford ST, Buske FA, Saar K, Hì¼bner N, Brì¤ndli AW, and Schedl,A

Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. - 2014 - Nature cell biology - 16 P367-75 - Chau YY, Bandiera R, Serrels A, Martì­nez-Estrada OM, Qing W, Lee M, Slight J, Thornburn A, Berry R, McHaffie S, Stimson RH, Walker BR, Chapuli RM, Schedl A, and Hastie,N

WT1 Maintains Adrenal-Gonadal Primordium Identity and Marks a Population of AGP-like Progenitors within the Adrenal Gland. - 2013 - Dev Cell - 27 P5-18 - Bandiera R, Vidal VP, Motamedi FJ, Clarkson M, Sahut-Barnola I, von Gise A, Pu WT, Hohenstein P, Martinez A, and Schedl,A

WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad. - 2012 - Development - 139 P4461-72 - Chassot AA, Bradford ST, Auguste A, Gregoire EP, Pailhoux E, de Rooij DG, Schedl A, and Chaboissier,MC

Testicular differentiation occurs in absence of R-spondin1 and Sox9 in mouse sex reversals. - 2012 - PLoS Genet - 8 Pe1003170 - Lavery R, Chassot AA, Pauper E, Gregoire EP, Klopfenstein M, de Rooij DG, Mark M, Schedl A, Ghyselinck NB, and Chaboissier,MC

A novel approach to selectively target neuronal subpopulations reveals genetic pathways that regulate tangential migration in the vertebrate hindbrain. - 2011 - PLoS Genet - 7 Pe1002099 - Benzing K, Flunkert S, Schedl A, and Engelkamp,D

The podocyte protein nephrin is required for cardiac vessel formation. - 2011 - Hum Mol Genet - 20 P2182-94 - Wagner N, Morrison H, Pagnotta S, Michiels JF, Schwab Y, Tryggvason K, Schedl A, and Wagner,KD

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Schedl Andreas
Group Leader

2009 Award of the French kidney foundation (Fondation du Rein)

2003 Avenir (INSERM, France)

2002 Philippe Leverhulme Prize (UK)

2001 EMBO Young Investigator Programme

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Members Team
Researchers
   Vidal Valérie
PreDocs
   Da Silva Fabio
   Grabek Anaëlle
   Kozlov Vladimir
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   Jian Motamedi Fariba
   Massa Filippo
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JOB OFFERS

    March 2013 - Andres Schedl Team
   1 CDD 30 mois Assistant ingenieur   Closed

    October 2012 - Andreas Schedl Team
   1 CDD 30 mois Assistant ingenieur   Closed

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CNRS UMR7277, Inserm U1091, UNS Université Nice Sophia Antipolis
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