Developmental defects and neuromuscular alterations due to mitofusin 2 gene (MFN2) silencing in zebrafish: a new model for Charcot-Marie-Tooth type 2A neuropathy.
The development of new animal models is a crucial step in determining the pathological mechanism underlying neurodegenerative diseases and is essential for the development of effective therapies. We have investigated the zebrafish (Danio rerio) as a new model to study CMT2A, a peripheral neuropathy characterized by the selective loss of motor neurons, caused by mutations of mitofusin 2 gene. Using a knock-down approach, we provide evidence that during embryonic development, mitofusin 2 loss of function is responsible of several morphological defects and motility impairment. Immunohistochemical investigations, revealing the presence of severe alterations in both motor neurons and muscles fibres, indicated the central role played by MFN2 in axonal and neuromuscular development. Finally, we demonstrated the ability of human MFN2 to balance the downregulation of endogenous mfn2 in zebrafish, further supporting the conserved function of the MFN2 gene. These results highlight the essential role of mitofusin 2 in the motor axon development and demonstrate the potential of zebrafish as a suitable and complementary platform for dissecting pathogenetic mechanisms of MFN2 mutations in vivo.
Vettori
Andrea
A
Department of Biology, University of Padua, Padua, Italy.
Bergamin
Giorgia
G
Moro
Enrico
E
Vazza
Giovanni
G
Polo
Giulia
G
Tiso
Natascia
N
Argenton
Francesco
F
Mostacciuolo
Maria Luisa
ML
D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D019295:Computational Biology; D002658:Developmental Disabilities / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004625:Embryo, Nonmammalian; D020558:GTP Phosphohydrolases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009468:Neuromuscular Diseases / Q000209:etiology* / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects*; D012333:RNA, Messenger / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D014404:Tubulin; D029961:Zebrafish Proteins; D055394:Tolloid-Like Metalloproteinases; C504338:tll1 protein, zebrafish; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human