Zebrafish mitofusin-2 knockdown: a new model for CMT2A neuropathy?

Mitofusin 2 (MFN2) is a large dynamin-like GTPase protein, located in the outer membrane of mitochondria and at the surface of the endoplasmic reticulum. Mfn2 is essential to maintain the organization of mitochondria in cells and it may play a role in the modulation of calcium exchanges between these two cellular compartments. MFN2 gene mutations are associated with Charcot-Marie-Tooth disease type 2A (CMT2A), an hereditary axonal neuropathy characterized by distal muscle weakness and atrophy. To investigate the function of this gene and its role in the pathogenesis of CMT2A, we have identified the zebrafish MFN2 ortholog and used a morpholino antisense oligonucleotide to knockdown mitofusin function. Morphant embryos showed motor impairment. Morphologically they displayed curved tails, disorganized somites, small and underdeveloped eyes and an extensive dilatation of the brain ventricles. Interestingly, this phenotype resembles the central nervous system abnormalities and optic atrophy observed in some CMT2A patients. Shorter and abnormal motor neuron axons were observed on 48 hpf morphant larvae, suggesting that these alterations are likely related to the movement deficits observed in morphants at this stage. Our preliminary results suggest that the abnormalities observed in MFN2 morphants are consistent with the human pathology. Given that a reliable animal model for CMT2A is still lacking, we propose zebrafish as a new and useful tool to dissect the pathogenetic mechanisms underlying CMT2A.