Intestinal stem cell specification during embryogenesis
1 PhD project offered in the IPP summer call 2019
The small intestine has a number of vital functions, including absorption of nutrients, secretion of hormones and host defence against microorganisms. These functions of the small intestine depend on the correct specification and maintenance of differentiated cell types within its innermost lining, the columnar epithelium. Intestinal epithelial cells are constantly challenged by harsh environment, pathogens and xenobiotics. To maintain tissue homeostasis, intestinal epithelial cells are fast renewed. This process is supported by intestinal stem cells (ISCs). Two ISC populations have been described in the adult intestinal epithelium. Both populations self-renew and give rise to differentiated post-mitotic lineages over long time. In contrast to well-characterized programs of the adult ISC maintenance and differentiation, little is known about their embryonic origin and their key regulators in development. The Soshnikova lab recently identified molecularly distinct embryonic progenitors that give rise to the adult ISCs. Furthermore, they found a key factor controlling the timing of ISC progenitor specification during embryogenesis. The goal of this PhD project is to understand whether ISC progenitors expressing different markers do indeed have different functions and generate different types of the adult ISCs.
PhD project: Defining functional heterogeneity within intestinal stem cell progenitors
To define all cell types within the developing small intestine the lab has performed single-cell RNA sequencing analysis. They have identified several molecularly distinct ISC progenitor populations. Furthermore, they have identified signalling molecules and their receptors that could be essential for the specific functions of these diverse progenitors. As a PhD student in the Soshnikova lab, you will use tools of mouse genetics combined with advanced imaging analysis and fluorescence activated cell sorting (FACS) to study fates of specific cell populations during normal homeostasis as well as in cancer formation (cell fate mapping analysis). Furthermore, you will define functions of a specific cell population by eliminating it in vivo, in embryo. In vivo analyses will be complemented by ex vivo 3D intestinal organoid assays. Finally, single-cell RNA-sequencing analysis will be used to identify adult epithelial cell types originating from distinct ISC progenitors. The results of this project will help to generate important hypotheses on the critical cell populations within the intestinal epithelium and transcriptional networks driving intestinal diseases such as inflammatory bowel disease and colorectal cancer.
Publications relevant to the project
Dzama MM, Nigmatullina L, Sayols S, Kreim N and Soshnikova N. (2017). Distinct populations of embryonic epithelial progenitors generate Lgr5+ intestinal stem cells. Dev Biol, 432: 258-264.
Kazakevych J, Sayols S, Messner B, Krienke C and Soshnikova N. (2017). Dynamic changes in chromatin states during specification and differentiation of adult intestinal stem cells. Nucleic Acids Res, 45: 5770-5784.
Nigmatullina L, Norkin M, Dzama MM, Messner B, Sayols S and Soshnikova N. (2017). Id2 controls specification of Lgr5(+) intestinal stem cell progenitors during gut development. EMBO J, 36: 869-885.