Project B09

Wnt-cilia signaling in epithelial polarization and renal development

Project leaders:  Gislene Pereira and Matias Simons

Abstract

Renal development is a complex process that is initiated by the conversion of the undifferentiated metanephric mesenchyme into a functional tubular epithelium, the nephron. Wnt signaling plays a key role in this mesenchymal-epithelial-transition (MET): first, canonical Wnt9b secreted by the invading ureteric bud is required for the expansion and commitment of nephron progenitors within the mesenchyme, and then, noncanonical Wnt4 induced by Wnt9b promotes epithelial tube formation. Previous studies have also suggested that primary cilia can mediate a switch from canonical to non-canonical signaling and that defects in cilia formation or disassembly cause renal disease, so-called ciliopathies (Simons et al., 2005 Nat Genet). Yet, whether this process functionally involves ciliogenesis and whether ciliopathies can indeed have their origins in early renal development remains unclear.

Here, we will study how Wnt signaling influences ciliogenesis during MET and, vice versa, how cilia drive epithelialization by suppressing canonical Wnt signaling. By combining the expertises of our two labs, the first aim will be to explore the mechanisms by which Wnt activation suppresses ciliogenesis in 2D epithelial cell culture models. For this, we will use a combination of proteomics and microscopy approaches to identify Wnt branches that regulate ciliogenesis and the molecular mechanisms involved in this regulation. In the second aim, we will study the role of cilia formation for early renal development using adhesive micropatterns and 3D renal organoids. In particular, we will study the temporal correlation of MET, ciliogenesis and the suppression of canonical Wnt signaling. Finally, we want to employ renal organoids and mice to study how lack of the ciliopathy protein inversin affects cilia formation, Wnt signaling and epithelial morphogenesis during MET. Altogether, our project will provide novel insights into the molecular role of Wnts during cilia biogenesis and into the contributions of cilia to the fine-tuning of Wnt signaling during organ development.

Project-related publications

  • Viol, L., S. Hata, A. Pastor-Peidro, A. Neuner, F. Murke, P. Wuchter, A.D. Ho, B. Giebel, and G. Pereira. 2020.
    Nek2 kinase displaces distal appendages from the mother centriole prior to mitosis. J. Cell Biol. 219:
    e201907136 PMID: 32211891
  • Fueller, J., M. Meurer, K. Herbst, K. Gubicza, K. Kurtulmus, J.D. Knopf, D. Kirrmaier, B. Buchmuller, G. Pereira, M.K. Lemberg, and M. Knop. 2020. CRISPR/Cas12a-assisted PCR tagging of mammalian genes. J. Cell Biol. 219:e201910210. PMID: 32406907
  • Marchesin, V., A. Perez-Marti, G. Le Meur, R. Pichler, K. Grand, E.D. Klootwijk, A. Kesselheim, R. Kleta, S.
    Lienkamp, and M. Simons. 2019. Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A. Cell Rep. 29:4407-4421 e4405. PMID: 31875549
  • Hermle, T., M.C. Guida, S. Beck, S. Helmstadter, and M. Simons. 2013. Drosophila ATP6AP2/VhaPRR functions both as a novel planar cell polarity core protein and a regulator of endosomal trafficking. EMBO J. 32:245-259. PMID: 23292348
  • Kuhns, S., K.N. Schmidt, J. Reymann, D.F. Gilbert, A. Neuner, B. Hub, R. Carvalho, P. Wiedemann, H.
    Zentgraf, H. Erfle, U. Klingmuller, M. Boutros, and G. Pereira. 2013. The microtubule affinity regulating kinase MARK4 promotes axoneme extension during early ciliogenesis. J. Cell Biol. 200:505-522. PMID: 23400999
  • Schmidt, K.N., S. Kuhns, A. Neuner, B. Hub, H. Zentgraf, and G. Pereira. 2012. Cep164 mediates vesicular
    docking to the mother centriole during early steps of ciliogenesis. J. Cell Biol. 199:1083-1101. PMID: 23253480
  • Hermle, T., D. Saltukoglu, J. Grunewald, G. Walz, and M. Simons. 2010. Regulation of Frizzled-dependent
    planar polarity signaling by a V-ATPase subunit. Curr Biol. 20:1269-1276. PMID: 20579879
  • Simons, M., W.J. Gault, D. Gotthardt, R. Rohatgi, T.J. Klein, Y. Shao, H.J. Lee, A.L. Wu, Y. Fang, L.M. Satlin, J.T. Dow, J. Chen, J. Zheng, M. Boutros, and M. Mlodzik. 2009. Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization. Nat Cell Biol. 11:286-294. PMID: 19234454
  • Simons, M., J. Gloy, A. Ganner, A. Bullerkotte, M. Bashkurov, C. Kronig, B. Schermer, T. Benzing, O.A. Cabello, A. Jenny, M. Mlodzik, B. Polok, W. Driever, T. Obara, and G. Walz. 2005. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet. 37:537-543. PMID: 15852005