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

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.

The knockout zebrafish line: a model to study Vici syndrome.

The EPG5 protein is a RAB7A effector involved in fusion specificity between autophagosomes and late endosomes or lysosomes during macroautophagy/autophagy. Mutations in the human gene cause a rare and severe multisystem disorder called Vici syndrome. In this work, we show that zebrafish mutants from both heterozygous and incrossed homozygous matings are viable and can develop to the age of sexual maturity without conspicuous defects in external appearance.

FGF signaling deregulation is associated with early developmental skeletal defects in animal models for mucopolysaccharidosis type II (MPSII).

Skeletal abnormalities represent a major clinical burden in patients affected by the lysosomal storage disorder mucopolysaccharidosis type II (MPSII, OMIM #309900). While extensive research has emphasized the detrimental role of stored glycosaminoglycans (GAGs) in the bone marrow (BM), a limited understanding of primary cellular mechanisms underlying bone defects in MPSII has hampered the development of bone-targeted therapeutic strategies beyond enzyme replacement therapy (ERT). We here investigated the involvement of key signaling pathways related to the loss of iduronate-2-sulfatase activity in two different MPSII animal models, D.

Perturbations in cell signaling elicit early cardiac defects in mucopolysaccharidosis type II.

Morphogens release and activity can be negatively affected by an impaired glycosaminoglycans (GAGs) turnover and proteoglycans assembly in the extracellular matrix, leading to altered tissue morphogenesis. In this work, we show that loss of Iduronate-2-sulfatase (IDS) activity, affecting GAGs catabolism and responsible for a life-threatening valvulopathy in mucopolysaccharidosis type II (MPSII), triggers early Sonic Hedgehog (Shh) and Wnt/β-catenin signaling defects, leading to aberrant heart development and atrioventricular valve formation in a zebrafish model. In addition, we consistently found impaired Shh signaling activity and cardiac electrophysiological abnormalities in IDS knockout mice at postnatal stages before any evident massive GAGs accumulation.

Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling.

Loss of lysosomal glucocerebrosidase (GBA1) function is responsible for several organ defects, including skeletal abnormalities in type 1 Gaucher disease (GD). Enhanced bone resorption by infiltrating macrophages has been proposed to lead to major bone defects. However, while more recent evidences support the hypothesis that osteoblastic bone formation is impaired, a clear pathogenetic mechanism has not been depicted yet.