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. These results suggest that IDS activity substantially affect cardiac morphogenesis through impaired Shh signaling and document an unexplored role of the enzyme in the fine-tuning of cell signaling pathways.
Department of Molecular Medicine.
Roberto
R
Costa
Department of Biology.
Andrea
A
Urbani
Department of Women's and Children's Health, University of Padova, I-35131 Padova, Italy.|Pediatric Research Institute "Città della Speranza," I-35127 Padova, Italy.
Marika
M
Salvalaio
Department of Women's and Children's Health, University of Padova, I-35131 Padova, Italy.
Stefania
S
Bellesso
Department of Biomedical Sciences, University of Padova, I-35131 Padova, Italy.
Domenico
D
Cieri
Department of Molecular Medicine.
Ilaria
I
Zancan
Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche Istituto Giannina Gaslini, I-16147 Genova, Italy.
Mirella
M
Filocamo
Department of Molecular Medicine.
Paolo
P
Bonaldo
Department of Biology.
Ildiko
I
Szabò
Department of Women's and Children's Health, University of Padova, I-35131 Padova, Italy.
Rosella
R
Tomanin
Department of Molecular Medicine.
Enrico
E
Moro
D000818:Animals; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D007066:Iduronate Sulfatase; D051379:Mice; D018345:Mice, Knockout; D016532:Mucopolysaccharidosis II / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism; D051176:beta Catenin
D006023:Glycoproteins; D006025:Glycosaminoglycans; D053823:Hedgehog Proteins; C018322:IDS protein, human; D011509:Proteoglycans; C524053:Shha protein, zebrafish; D029961:Zebrafish Proteins; D051176:beta Catenin; D007066:Iduronate Sulfatase