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The Journal of Neuroscience, January 3, 2007, 27(1):4-14; doi:10.1523/JNEUROSCI.3825-06.2007

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Development/Plasticity/Repair
DISC1 Regulates Neurotrophin-Induced Axon Elongation via Interaction with Grb2

Tomoyasu Shinoda,¹ Shinichiro Taya,¹ Daisuke Tsuboi,¹ Takao Hikita,¹ Reiko Matsuzawa,¹ Setsuko Kuroda,¹ Akihiro Iwamatsu,² and Kozo Kaibuchi¹

¹Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa, Nagoya 466-8550, Japan, and ²Protein Research Network, Yokohama 236-0004, Japan

Correspondence should be addressed to Dr. Kozo Kaibuchi, Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya 466-8550, Japan. Email: kaibuchi{at}med.nagoya-u.ac.jp

Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras–extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.

Key words: DISC1; neurotrophin; Grb2; axon elongation; ERK; schizophrenia

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Received Sept. 2, 2006; revised Oct. 31, 2006; accepted Nov. 1, 2006.

Correspondence should be addressed to Dr. Kozo Kaibuchi, Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya 466-8550, Japan. Email: kaibuchi{at}med.nagoya-u.ac.jp

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