A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

Roberto Costa, Stefania Bellesso, Susanna Lualdi, Rosa Manzoli, Valeria Pistorio, Mirella Filocamo, Enrico Moro

Research output: Contribution to journalArticlepeer-review

Abstract

Bone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3' untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function.

Original languageEnglish
Pages (from-to)274-285
Number of pages12
JournalHuman Molecular Genetics
Volume29
Issue number2
DOIs
Publication statusPublished - Jan 15 2020

Keywords

  • 3' Untranslated Regions
  • Adaptor Proteins, Vesicular Transport/genetics
  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Disease Models, Animal
  • Dishevelled Proteins/genetics
  • Gaucher Disease/enzymology
  • Glucosylceramidase/genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Membrane Proteins/genetics
  • MicroRNAs/genetics
  • Osteoblasts/enzymology
  • Transcription, Genetic
  • Wnt Signaling Pathway/genetics
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics

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