Regulation of dendritic spine morphogenesis by insulin receptor substrate 53, a downstream effector of Rac1 and Cdc42 small GTPases

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.
Publisher
SOC NEUROSCIENCE
Issue Date
2005-01
Language
ENG
Keywords

INSULIN-RECEPTOR SUBSTRATE; POSTSYNAPTIC DENSITY FRACTION; ARP2/3 COMPLEX; GUANYLATE KINASES; SYNAPTIC FUNCTION; EXCHANGE FACTOR; PROTEIN-KINASE; SHANK FAMILY; PSD-95; ACTIN

Citation

JOURNAL OF NEUROSCIENCE, v.25, no.4, pp.869 - 879

ISSN
0270-6474
DOI
10.1523/JNEUROSCI.3212-04.2005
URI
http://hdl.handle.net/10203/1599
Appears in Collection
BS-Journal Papers(저널논문)
Files in This Item
000226577000012.pdf(981.15 kB)Download
  • Hit : 457
  • Download : 370
  • Cited 0 times in thomson ci
This item is cited by other documents in WoS
⊙ Detail Information in WoSⓡClick to seewebofscience_button
⊙ Cited 111 items in WoSClick to see citing articles inrecords_button

qr_code

  • mendeley

    citeulike


rss_1.0 rss_2.0 atom_1.0