Project A08

Wnt Pathway Specificity in Niche – Stem Cell Control

Project leaders:  Josephine Bageritz and Ingrid Lohmann

Abstract

Wnt signaling in stem cell niches carries out highly cell type and context specific functions to control stem cell behavior, maintenance of potency or differentiation as well as division mode. However, how such specificity is encoded by a single signaling system is still unclear. We will use two major stem cell systems in Drosophila, the larval epithelial-muscle stem cell niche and the adult male germline stem cell niche, to elucidate the mechanisms employed by Wnt to elicit differential stem cell responses during development and in adult life. These two stem cell niches are ideal models for tackling this question. On the one hand, they share important aspects, such as signaling pathways acting with Wnt in the control of stem cell behavior, allowing us to examine conserved mechanisms. On the other hand, they exhibit also divergent features, which we will exploit to identify system specific components driving specificity in Wnt-dependent cellular responses. In the epithelial-muscle stem cell niche so far one Wnt ligand, Wingless (Wg), has been shown to act on a rather homogenous cell population controlling specification and different division modes of two subpopulations of adult muscle stem cells (AMPs). In contrast, preliminary work of the I. Lohmann group revealed that at least two distinct Wnts (Wnt2 and Wnt4) control the behavior of two very different stem cell types, the somatic and germline stem cells, in a paracrine and possibly also autocrine fashion in the male germline stem cell niche. Previous data from J. Bageritz identified a novel regulator of Wnt signaling in the epithelial-muscle stem cell niche, CG5151, which is a likely candidate to control the cross-talk between Wnt/Wg and TGF-β/Activin signaling in this system. Based on these findings, we will now test our hypotheses that Wnt signaling output in neighboring stem cell populations is controlled in a context-dependent manner by a specific Wnt code driving different responses in individual cells, a cross-talk of Wnt signaling activity with other signaling pathways modulating their activities and the induction of specific Wnt output effectors resulting in a differential behavior of (stem) cells. To this end, we will explore cellular heterogeneity in the Wnt code by systematically disentangling the role of Wnt ligands secreted from the niche as well as Wnt receptors in the receiving stem cell populations. Cellular response will be assessed using imaging to determine stem cell pool size and consequences on cellular specification. To elucidate how pathway crosstalk with Wnt signaling impacts stem cell heterogeneity, we will monitor cell-type specific responses to pathway modulation in the two stem cell niches using cell-specific analyses and single-cell RNA sequencing. Taken together, our integrated research project will lead to important insights into the mechanisms employed by stem cells to translate Wnt signaling inputs into appropriate behavior and shed light onto so far underexplored heterogeneity in two dynamic stem cell systems.

Project-related publications

  • Carnesecchi, J., G. Sigismondo, K. Domsch, C.E.P Baader, M.R. Rafiee, J. Krijgsveld, and I. Lohmann. 2020. Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity. Nat. Commun. 13;11(1):1388. PMID: 32170121
  • Sorge, S., J. Theelke , K. Yildirim, H. Hertenstein, E. McMullen, S. Müller, C. Altbürger, S. Schirmeier, and I. Lohmann. 2020. ATF4-induced Warburg Metabolism drives Over-proliferation in Drosophila. Cell Rep. 31:107659. PMID: 32433968
  • Velten, J., R. Agarwal, P. van Nierop y Sanchez, L. Bognar, M. Paulsen, L. Velten, and I. Lohmann. 2020. The molecular logic of synaptic wiring at the single cell level. bioRxiv doi.org/10.1101/2020.11.30.402057
  • Carnesecchi, J., and I. Lohmann. 2020. Closing the gap: a roadmap to single-cell regulatory genomics. Mol. Syst. Biol. 16(5):e9497. PMID: 32430985
  • Bageritz, J., and G. Raddi. 2019. Single-Cell RNA Sequencing with Drop-Seq. In Single Cell Methods: Sequencing and Proteomics. V. Proserpio, editor. Springer New York, New York, NY. 73–85. PMID: 31028633
  • Bageritz, J., P. Willnow, E. Valentini, S. Leible, M. Boutros, and A.A. Teleman. 2019. Gene expression atlas of a developing tissue by single cell expression correlation analysis. Nat. Methods 16:750–756. PMID: 31363221
  • Tamirisa, S., F. Papagiannouli, E. Rempel, O. Ermakova, N. Trost, J. Zhou, J. Mundorf, S. Brunel, N. Ruhland, M. Boutros, J. U Lohmann, and I. Lohmann. 2018. Decoding the regulatory logic of the Drosophila male stem cell system. Cell Rep. 24: 3072-3086. PMID: 30208329
  • Trost, N., E. Rempel, O. Ermakova, S. Tamirisa, L. Pârcălăbescu, M. Boutros, J. U. Lohmann, and I. Lohmann. 2018. WEADE: a workflow for enrichment analysis and data exploration. PLoS One 28;13(9):e0204016. PMID: 30265728
  • Martins, L., R. Bung, S. Koch, K. Richter, L. Schwarzmüller, B. Kurtulmus, C. Niehrs, A. Rouhi, I. Lohmann, G. Pereira, S. Fröhling, H. Glimm and C. Scholl. 2017. Stk33 is required for spermatid differentiation and male fertility in mice. Dev. Biol. 433:84-93. PMID: 29155043
  • Papagiannouli, F., L. Schardt, J. Grajcarek, N. Ha, P. Kaspar, and I. Lohmann. 2014. The Hox gene Abd-B controls stem cell niche function in the Drosophila testis. Dev. Cell 27: 189-202. PMID: 24480643