Regulation of Wnt signal transduction

Christa Janine van der Veen

Research output: ThesisDoctoral thesis 2 (Research NOT UU / Graduation UU)

Abstract

Cell migration is a fundamental process in the development of animals. The development of an organism from a unicellular zygote into a fully functional adult multicellular organism, is a highly complex process. These are tightly controlled, both temporally and spatially. Consequently, failure of cells to migrate or migration to inappropriate locations can result in various diseases, for example tumor formation and metastasis. Understanding cell migration during development on a molecular level is essential to help potentially develop novel therapeutic approaches. A major developmental pathway depending on morphogens is the Wnt signaling pathway. Wnt proteins are secreted, lipid-modified glycoproteins that provide positional information to cells during development. The Wnt signaling pathway is evolutionary conserved in vertebrates and invertebrates. In addition to its role in development, Wnt signaling is important during adult life for stem cell maintenance and tissue-homeostasis, and as a consequence, deregulation of Wnt signaling is frequently observed in cancer. Wnt signaling is complex, with vertebrate genomes containing 19 different Wnts. With 19 ligands and 10 possible receptors, the number of possible interactions is staggering. Downstream of these ligands and receptors, the Wnt signaling pathway can be divided into two major classes, the canonical Wnt/-catenin-dependent pathway, and the non-canonical beta-catenin-independent pathway. In this thesis, various Wnt signal transduction pathways and how they are regulated are discussed with a focus on the non-canonical Wnt pathway, in various neuronal cell migrations and developmental processes in the model organism C. elegans. First, a review is provided about what is currently known about an important non-canonical Wnt pathway – Wnt/Ror signaling. We focus on various developmental functions and signaling mechanisms in vertebrate development and the nematode C. elegans. In addition, we discuss how new insights in a cell non-autonomous role of Ror in C. elegans may help understand the role of Ror in cancer. Second, the role of the C. elegans Ror ortholog CAM-1 in QR.p neuroblast migration is investigated, and CAM-1 is shown to have both cell autonomous and non-cell autonomous functions. Moreover, surprisingly, CAM-1 is responsible for the extracellular spreading of two Wnts, EGL-20 and CWN-1, in the posterior region of the worm. Furthermore, a role for glypicans is found in shaping of EGL-20 Wnt gradients. The protein CAM-1 is further investigated to identify the role of the protein’s domains. Various neuronal migrations rely on the Wnt-binding cysteine-rich domain (CRD) of CAM-1. However, migration of various neurons are shown to depend on different intracellular domains, indicating that CAM-1 can trigger different signaling pathways, both kinase-dependent and -independent. Moreover, Dishevelled proteins are shown to act partially redundantly as downstream effectors of CAM-1 in QR.p migration. Lastly, the transcriptional regulation by the Hox transcription factors mab-5 and lin-39 is addressed, both of which are essential for the migration of the QL and QR neuroblast descendants respectively. mab-5 expression is shown to be regulated by negative feedback through the E3 ligase PLR-1/ZNRF3/RNF43, ensuring robust expression. LIN-39 regulates the expression of three genes acting in parallel in anterior migration of QR.p: mig-13, mom-5, and cam-1.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Utrecht University
Supervisors/Advisors
  • Korswagen, Hendrik, Primary supervisor
Award date6 Jul 2022
Place of PublicationUtrecht
Publisher
Print ISBNs978-94-6458-296-3
DOIs
Publication statusPublished - 6 Jul 2022

Keywords

  • Cell migration
  • Wnt
  • developmental biology
  • morphogens
  • C. elegans,: Ror signaling

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