Developmental defects and neuromuscular alterations due to mitofusin 2 gene (MFN2) silencing in zebrafish: a new model for Charcot-Marie-Tooth type 2A neuropathy

Andrea Vettori; Giorgia Bergamin; Enrico Moro; Giovanni Vazza; Giulia Polo; Natascia Tiso; Francesco Argenton; Maria Luisa Mostacciuolo

doi:10.1016/j.nmd.2010.09.002

Developmental defects and neuromuscular alterations due to mitofusin 2 gene (MFN2) silencing in zebrafish: a new model for Charcot-Marie-Tooth type 2A neuropathy

Neuromuscul Disord. 2011 Jan;21(1):58-67. doi: 10.1016/j.nmd.2010.09.002. Epub 2010 Oct 14.

Authors

Andrea Vettori¹, Giorgia Bergamin, Enrico Moro, Giovanni Vazza, Giulia Polo, Natascia Tiso, Francesco Argenton, Maria Luisa Mostacciuolo

Affiliation

¹ Department of Biology, University of Padua, Padua, Italy.

PMID: 20951042
DOI: 10.1016/j.nmd.2010.09.002

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Body Patterning / drug effects
Body Patterning / genetics
Charcot-Marie-Tooth Disease* / chemically induced
Charcot-Marie-Tooth Disease* / complications
Charcot-Marie-Tooth Disease* / genetics
Computational Biology
Developmental Disabilities / etiology*
Developmental Disabilities / genetics
Disease Models, Animal
Down-Regulation / drug effects*
Down-Regulation / genetics
Embryo, Nonmammalian
GTP Phosphohydrolases
Humans
Membrane Proteins / genetics
Mitochondrial Proteins / genetics
Motor Activity / drug effects
Motor Activity / genetics
Neuromuscular Diseases / etiology*
Neuromuscular Diseases / genetics
Oligodeoxyribonucleotides, Antisense / adverse effects*
RNA, Messenger / metabolism
Receptors, Cholinergic / metabolism
Tolloid-Like Metalloproteinases / genetics*
Tolloid-Like Metalloproteinases / metabolism
Tubulin / metabolism
Zebrafish
Zebrafish Proteins / genetics*
Zebrafish Proteins / metabolism

Substances

Membrane Proteins
Mitochondrial Proteins
Oligodeoxyribonucleotides, Antisense
RNA, Messenger
Receptors, Cholinergic
Tubulin
Zebrafish Proteins
Tolloid-Like Metalloproteinases
tll1 protein, zebrafish
GTP Phosphohydrolases
MFN2 protein, human