Disruption of SMN function by ectopic expression of the human SMN gene in Drosophila

Spinal muscular atrophy is a neurodegenerative disorder caused by mutations or deletions in the survival motor neuron (SMN) gene. We have cloned the D rosophila ortholog of SMN (DmSMN) and disrupted its function by ectopically expressing human SMN. This leads to pupal lethality caused by a dominant-n egative effect, whereby human SMN may bind endogenous DmSMN resulting in no n-functional DmSMN/human SMN hetero-complexes. Ectopic expression of trunca ted versions of DmSMN and yeast two-hybrid analysis show that the C-terminu s of SMN is necessary and sufficient to replicate this effect. We have ther efore generated a system which can be utilized to carry out suppressor and high-throughput screens, and provided in vivo evidence for the importance o f SMN oligomerization for SMN function at the level of an organism as a who le. (C) 2000 Federation of European Biochemical Societies. Published by Els evier Science B.V. All rights reserved.