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Molecular and Cellular Biology, September 2006, p. 6923-6935, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.02474-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Solo/Trio8, a Membrane-Associated Short Isoform of Trio, Modulates Endosome Dynamics and Neurite Elongation

Ying-Jie Sun,^1,5, Kaori Nishikawa,^1,3, Hideki Yuda,¹ Yu-Lai Wang,¹ Hitoshi Osaka,³ Nobuna Fukazawa,^1,4 Akira Naito,⁵ Yoshihisa Kudo,⁴ Keiji Wada,^1,7 and Shunsuke Aoki^1,2,6,7*

Department of Degenerative Neurological Diseases,¹ Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan,² Japan Science and Technology Agency (JST), Kawaguchi, Saiatama 332-0012, Japan,³ Laboratory of Cellular Neurobiology, Tokyo University of Pharmacology and Life Science, Hachioji, Tokyo 192-0392, Japan,⁴ Department of Anatomy and Structural Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan; New Energy and Industrial Technology Development Organization (NEDO), Kawasaki, Kanagawa 212-8554, Japan; and JST,CREST, Kawaguchi, Saitama 332-0012, Japan,⁵ Department of Anatomy and Structural Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan; New Energy and Industrial Technology Development Organization (NEDO), Kawasaki, Kanagawa 212-8554, Japan,⁶ JST,CREST, Kawaguchi, Saitama 332-0012, Japan⁷

Received 28 December 2005/ Returned for modification 15 February 2006/ Accepted 28 June 2006

With DNA microarrays, we identified a gene, termed Solo, that is downregulated in the cerebellum of Purkinje cell degeneration mutant mice. Solo is a mouse homologue of rat Trio8—one of multiple Trio isoforms recently identified in rat brain. Solo/Trio8 contains N-terminal sec14-like and spectrin-like repeat domains followed by a single guanine nucleotide exchange factor 1 (GEF1) domain, but it lacks the C-terminal GEF2, immunoglobulin-like, and kinase domains that are typical of Trio. Solo/Trio8 is predominantly expressed in Purkinje neurons of the mouse brain, and expression begins following birth and increases during Purkinje neuron maturation. We identified a novel C-terminal membrane-anchoring domain in Solo/Trio8 that is required for enhanced green fluorescent protein-Solo/Trio8 localization to early endosomes (positive for both early-endosome antigen 1 [EEA1] and Rab5) in COS-7 cells and primary cultured neurons. Solo/Trio8 overexpression in COS-7 cells augmented the EEA1-positive early-endosome pool, and this effect was abolished via mutation and inactivation of the GEF domain or deletion of the C-terminal membrane-anchoring domain. Moreover, primary cultured neurons transfected with Solo/Trio8 showed increased neurite elongation that was dependent on these domains. These results suggest that Solo/Trio8 acts as an early-endosome-specific upstream activator of Rho family GTPases for neurite elongation of developing Purkinje neurons.

Y.-J.S. and K.N. contributed equally to this work.

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