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Vol. 17, Issue 3, 1273-1285, March 2006

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Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2

Takashi Nishimura ^*, Tomoya Yamaguchi ^*, Akinori Tokunaga , Akitoshi Hara ^*, Tomonari Hamaguchi ^*, Katsuhiro Kato ^*, Akihiro Iwamatsu , Hideyuki Okano , and Kozo Kaibuchi ^*

^* Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan; Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; and Central Laboratories for Key Technology, Kirin Brewery Company, Yokohama, Kanagawa 236-0004, Japan

Submitted August 1, 2005; Revised November 15, 2005; Accepted December 27, 2005
Monitoring Editor: Robert Parton

Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Kozo Kaibuchi (kaibuchi{at}med.nagoyau.ac.jp).

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