CMT 2A: Developmental defects and neuromuscular alterations due to mitofusin 2 g

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Neuromuscul Disord. 2010 Oct 13

Developmental defects and neuromuscular alterations due to mitofusin 2 gene

(MFN2) silencing in zebrafish: A new model for Charcot-Marie-Tooth type 2A

neuropathy.

Vettori A, Bergamin G, Moro E, Vazza G, Polo G, Tiso N, Argenton F, Mostacciuolo

ML.

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

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.