PT  - JOURNAL ARTICLE
AU  - Jeonghoon Choi
AU  - Jaewon Ko
AU  - Bence Racz
AU  - Alain Burette
AU  - Jae-Ran Lee
AU  - Seho Kim
AU  - Moonseok Na
AU  - Hyun Woo Lee
AU  - Karam Kim
AU  - Richard J. Weinberg
AU  - Eunjoon Kim
TI  - Regulation of Dendritic Spine Morphogenesis by Insulin Receptor Substrate 53, a Downstream Effector of Rac1 and Cdc42 Small GTPases
AID  - 10.1523/JNEUROSCI.3212-04.2005
DP  - 2005 Jan 26
TA  - The Journal of Neuroscience
PG  - 869--879
VI  - 25
IP  - 4
4099  - http://www.jneurosci.org/content/25/4/869.short
4100  - http://www.jneurosci.org/content/25/4/869.full
SO  - J. Neurosci.2005 Jan 26; 25
AB  - The small GTPases Rac1 and Cdc42 are key regulators of the morphogenesis of actin-rich dendritic spines in neurons. However, little is known about how activated Rac1/Cdc42 regulates dendritic spines. Insulin receptor substrate 53 (IRSp53), which is highly expressed in the postsynaptic density (PSD), is known to link activated Rac1/Cdc42 to downstream effectors for actin regulation in non-neural cells. Here, we report that IRSp53 interacts with two specific members of the PSD-95 family, PSD-95 and chapsyn-110/PSD-93, in brain. An IRSp53 mutant lacking the C-terminal PSD-95-binding motif shows significant loss of synaptic localization in cultured neurons. Overexpression of IRSp53 in cultured neurons increases the density of dendritic spines but does not affect their length or width. Conversely, short-interfering RNA-mediated knock-down of IRSp53 reduces the density, length, and width of spines. In addition, the density and size of spines are decreased by a dominant-negative IRSp53 with a point mutation in the Src homology 3 (SH3) domain and a dominant-negative proline-rich region of WAVE2 (Wiskott-Aldrich syndrome protein family Verprolin-homologous protein), a downstream effector of IRSp53 that binds to the SH3 domain of IRSp53. These results suggest that PSD-95 interaction is an important determinant of synaptic IRSp53 localization and that the SH3 domain of IRSp53 links activated Rac1/Cdc42 to downstream effectors for the regulation of spine morphogenesis.