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Alsin/Rac1 signaling controls survival and growth of spinal motoneurons.

Abstract : OBJECTIVE: Recessive mutations in alsin, a guanine-nucleotide exchange factor for the GTPases Rab5 and Rac1, cause juvenile amyotrophic lateral sclerosis (ALS2) and related motoneuron disorders. Alsin function in motoneurons remained unclear because alsin knock-out mice do not develop overt signs of motoneuron degeneration. METHODS: To generate an alsin loss-of-function model in an ALS-relevant cell type, we developed a new small interfering RNA electroporation technique that allows efficient knock down of alsin in embryonic rat spinal motoneurons. RESULTS: After small interfering RNA-mediated alsin knockdown, cultured motoneurons displayed a reduced apparent size of EEA1-labeled early endosomes and an increased intracellular accumulation of transferrin and L1CAM. Alsin knockdown induced cell death in 32 to 48% of motoneurons and significantly inhibited axon growth in the surviving neurons. Both cellular phenotypes were mimicked by expression of a dominant-negative Rac1 mutant and were completely blocked by expression of a constitutively active Rac1 mutant. Expression of dominant-negative or constitutively active forms of Rab5 had no such effects. INTERPRETATION: Our data demonstrate that alsin controls the growth and survival of motoneurons in a Rac1-dependant manner. The strategy reported here illustrates how small interfering RNA electroporation can be used to generate cellular models of neurodegenerative disease involving a loss-of-function mechanism.
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Contributor : Georg Haase Connect in order to contact the contributor
Submitted on : Tuesday, December 11, 2007 - 7:43:14 PM
Last modification on : Thursday, May 12, 2022 - 9:12:09 AM
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Arnaud Jacquier, Emmanuelle Buhler, Michael K. Schäfer, Delphine Bohl, Stéphane Blanchard, et al.. Alsin/Rac1 signaling controls survival and growth of spinal motoneurons.. Annals of Neurology, Wiley, 2006, 60 (1), pp.105-17. ⟨10.1002/ana.20886⟩. ⟨inserm-00195979⟩



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