Philippe JAY group: SELF-RENEWAL AND DIFFERENTIATION OF EPITHELIA
Department: Cancer biology - Research axis: Molecular & cellular networks

 

Research subject

We use the intestinal epithelium to study cellular dynamics in epithelia with a rapid turnover rate, and its alterations in cancer and inflammatory diseases. Our aim is to decipher gene networks and signalling pathways involved in the maintenance and differentiation of the intestinal epithelial stem cells, and in the function of differentiated epithelial cells regulating the interface between the host and its environment. Our experimental approach relies on a combination of mouse genetics, molecular and cellular biology and analyses at the pan-genomic scale.

Function of the Sox9 transcription factor: Paneth cells represent one of the differentiated cell types of the intestinal epithelium. They secrete antimicrobial peptides regulating the intestinal microflora and contribute to the intestinal epithelial stem cell niche. We have been interested in the function of Sox9, which is strongly expressed in stem and Paneth cells (Blache et al., J. Cell Biol. 2004), as well as in tuft cells (Gerbe et al., J. Cell Biol. 2011). Constitutive deletion of the Sox9 gene in the intestinal epithelium results in the absence of the Paneth cell lineage (Bastide et al., J. Cell Biol. 2007). Our current objective is to understand the function of Sox9 in Paneth cells and stem cells.

Stem cells and cancer: Although the precise identity of the intestinal epithelium stem cells is still controversial, Lgr5-expressing cells at the crypt bottom have all the features expected from stem cells. We analysed the mode of chromosome segregation in intestinal epithelial stem cells and came to the conclusion that intestinal epithelial stem cells segregate their chromosomes randomly (Escobar et al, Nature Communications 2011). We are also interested in the role of cancer stem cells (CSC) during cancer relapse. This includes (1) the identification of new players involved in resistance of CSC to chemotherapy, to propose alternative strategies to decrease or eliminate resistance; (2) the role of circulating tumor cells with CSC properties in metastatic invasion; (3) role of post-translational regulation in CSC plasticity.

Function of tuft cells: Their unique morphology led to the identification of tuft cells (also called brush cells) more than half a century ago. Because of the lack of appropriate markers, they have long remained overlooked in functional studies of the intestinal epithelium.

We have characterised mouse and human intestinal epithelial tuft cells. These rare cells express the DCLK1 marker, previously considered as a putative quiescent stem cell marker in the intestinal epithelium (Gerbe et al., Gastroenterology 2009, vol. 137: 2179). We demonstrated that DCLK1+ cells are instead post-mitotic tuft cells, which are short lived and permanently renewed from Lgr5+ stem cells. According to their unique genetic requirements to differentiate, we proposed that tuft cells constitute a fifth differentiated cell type in the intestinal epithelium (Gerbe et al., J. Cell Biol. 2011, vol. 192: 767-780; Gerbe et al. CMLS 2012, vol. 69: 2907-2917). Together with other labs, we recently identified the first function of the intestinal tuft cells in initiating type 2 immune responses during infections with helminth parasites (Gerbe et al., Nature 2016; Gerbe et al., Mucosal Immunology 2016). Ongoing projects address the functions of tuft cells in various physiological or pathological situations.

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LINK TO TEAM WEB SITE

Team

Team leader

Philippe Jay
DR2, Inserm


  IGF Nord 107a

  04 34 35 92 98

 

Staff Jay/Jay

Nathalie Coutry
CRCN, Inserm


  IGF Nord 121a

  04 34 35 93 03

 

Laure Garnier
IE CDD, CNRS


  IGF Nord 103

  04 34 35 92 66

 

François Gerbe
CRCN, CNRS


  IGF Nord 121a

  04 34 35 93 03

 

Julie Nguyen
Doctorant(e), UM


  IGF Nord 103

 

 

Emmanuelle Sidot
Doctorant(e), UM


  IGF Nord 103

  04 34 35 92 66

 

Elisabeth Simboeck
Post-doctorant(e), CNRS


  IGMM

  04 34 35 92 98

 


Major publications

  • Gerbe F., Sidot E., Smyth D. J., Ohmoto M., Matsumoto I., Dardalhon V., Cesses P., Garnier L., Pouzolles M., Brulin B., Bruschi M., Harcus Y., Zimmermann V. S., Taylor N., Maizels R. M. and Jay P. : Intestinal epithelial tuft cells initiate type 2 mucosal responses to helminth parasites. Nature, vol. 529 : 226-230 (2016).
  • Gerbe F. and Jay P. : Intestinal tuft cells: epithelial sentinels linking luminal cues to the immune system. Mucosal Immunology, vol. 9 (6) : 1353-1359 (2016).
  • Gerbe F., Legraverend C. and Jay P. : The intestinal epithelium tuft cells: specification and function. Cellular and Molecular Life Sciences, 69(17) : 2907-2917 (2012).
  • Ecobar M., Nicolas P., Sangar F., Laurent-Chabalier S., Clair P., Joubert D., Jay P. and Legraverend C. : Intestinal epithelial stem cells do not protect a copy of their genome by asymmetric chromosome segregation. Nature Communications, 2 : 258 (2011).
  • Gerbe F., van Es J. H., Makrini L., Brulin B., Mellitzer G., Robine S., Romagnolo B., Shroyer N. F., Bourgaux J.-F., Pignodel C., Clevers H. and Jay P. : Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. The Journal of Cell Biology, vol. 192(5) : 767-780 (2011). Commentaire éditorial en page 706.
  • Gerbe F., Brulin B., Makrini L., Legraverend C. and Jay P. : DCAMKL-1 expression identifies tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology, vol. 137(6) : 2179-2180 (2009).
  • Bastide P., Darido C., Pannequin J., Kist R., Robine S., Marty-Double C., Bibeau F., Scherer G., Joubert D., Hollande F., Blache P. and Jay P. : Sox9 regulates cell proliferation ans is required for Paneth cell differentiation in the intestinal epithelium. The Journal of Cell Biology, vol. 178 (4) : 635-648 (2007).
 

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