SELF-RENEWAL AND DIFFERENTIATION OF EPITHELIA
Departement: Physiology and Cancer
Research subject
We use the intestinal epithelium as a model to study the key properties of epithelia with rapid turnover, and their alterations in cancer and chronic inflammatory diseases.
We are studying the gene networks and signalling pathways involved in the maintenance and differentiation of the intestinal epithelial stem cells, and in the function of differentiated 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 and secrete antimicrobial peptides regulating the intestinal microflora. 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 causes ablation 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). Additional projects are underway to understand the molecular bases of tumorigenesis.
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 since remained overlooked in functional studies of the intestinal epithelium.
We have recently 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).
Team
Major publications
- 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).
- TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization: impact on tumorigenesis. Macari F, El-Houfi Y, Boldina G, Xu H, Khoury-Hanna S, Ollier J, Yazdani L, Zheng G, Bièche I, Legrand N, Paulet D, Durrieu S, Byström A, Delbecq S, Lapeyre B, Bauchet L, Pannequin J, Hollande F, Pan T, Teichmann M, Vagner S, David A, Choquet A, Joubert D. Oncogene. 2016 Apr 7;35(14):1785-96.