A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC

Huaye Zhang, Donna J. Webb, Hannelore Asmussen, Shuang Niu, Alan F. Horwitz

Research output: Contribution to journalArticle

244 Citations (Scopus)

Abstract

Three of seven recently identified genes mutated in nonsyndromic mental retardation are involved in Rho family signaling. Two of the gene products, α-p-21-activated kinase (PAK) interacting exchange factor (αPIX) and PAK3, form a complex with the synaptic adaptor protein G-protein-coupled receptor kinase-interacting protein 1 (GIT1). Using an RNA interference approach, we show that GIT1 is critical for spine and synapse formation. We also show that Rac is locally activated in dendritic spines using fluorescence resonance energy transfer. This local activation of Rac is regulated by PIX, a Rac guanine nucleotide exchange factor. PAK1 and PAK3 serve as downstream effectors of Rac in regulating spine and synapse formation. Active PAK promotes the formation of spines and dendritic protrusions, which correlates with an increase in the number of excitatory synapses. These effects are dependent on the kinase activity of PAK, and PAK functions through phosphorylating myosin II regulatory light chain (MLC). Activated MLC causes an increase in dendritic spine and synapse formation, whereas inhibiting myosin ATPase activity results in decreased spine and synapse formation. Finally, both activated PAK and activated MLC can rescue the defects of GIT1 knockdown, suggesting that PAK and MLC are downstream of GIT1 in regulating spine and synapse formation. Our results point to a signaling complex, consisting of GIT1, PIX, Rac, and PAK, that plays an essential role in the regulation of dendritic spine and synapse formation and provides a potential mechanism by which αPIX and PAK3 mutations affect cognitive functions in mental retardation.

Original languageEnglish (US)
Pages (from-to)3379-3388
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number13
DOIs
StatePublished - Mar 30 2005
Externally publishedYes

Fingerprint

Morphogenesis
Synapses
Spine
Phosphotransferases
Dendritic Spines
Intellectual Disability
G-Protein-Coupled Receptor Kinases
Receptor-Interacting Protein Serine-Threonine Kinases
Myosin Type II
Guanine Nucleotide Exchange Factors
Myosin Light Chains
Fluorescence Resonance Energy Transfer
Myosins
RNA Interference
Protein Kinases
Cognition
Genes
Mutation

Keywords

  • Cytoskeleton
  • Dendritic spines
  • GIT1
  • MLC
  • PAK
  • PIX
  • Rac
  • Synaptogenesis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. / Zhang, Huaye; Webb, Donna J.; Asmussen, Hannelore; Niu, Shuang; Horwitz, Alan F.

In: Journal of Neuroscience, Vol. 25, No. 13, 30.03.2005, p. 3379-3388.

Research output: Contribution to journalArticle

Zhang, Huaye ; Webb, Donna J. ; Asmussen, Hannelore ; Niu, Shuang ; Horwitz, Alan F. / A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 13. pp. 3379-3388.
@article{9dbc6f84e49b422e96eba3502437c6e9,
title = "A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC",
abstract = "Three of seven recently identified genes mutated in nonsyndromic mental retardation are involved in Rho family signaling. Two of the gene products, α-p-21-activated kinase (PAK) interacting exchange factor (αPIX) and PAK3, form a complex with the synaptic adaptor protein G-protein-coupled receptor kinase-interacting protein 1 (GIT1). Using an RNA interference approach, we show that GIT1 is critical for spine and synapse formation. We also show that Rac is locally activated in dendritic spines using fluorescence resonance energy transfer. This local activation of Rac is regulated by PIX, a Rac guanine nucleotide exchange factor. PAK1 and PAK3 serve as downstream effectors of Rac in regulating spine and synapse formation. Active PAK promotes the formation of spines and dendritic protrusions, which correlates with an increase in the number of excitatory synapses. These effects are dependent on the kinase activity of PAK, and PAK functions through phosphorylating myosin II regulatory light chain (MLC). Activated MLC causes an increase in dendritic spine and synapse formation, whereas inhibiting myosin ATPase activity results in decreased spine and synapse formation. Finally, both activated PAK and activated MLC can rescue the defects of GIT1 knockdown, suggesting that PAK and MLC are downstream of GIT1 in regulating spine and synapse formation. Our results point to a signaling complex, consisting of GIT1, PIX, Rac, and PAK, that plays an essential role in the regulation of dendritic spine and synapse formation and provides a potential mechanism by which αPIX and PAK3 mutations affect cognitive functions in mental retardation.",
keywords = "Cytoskeleton, Dendritic spines, GIT1, MLC, PAK, PIX, Rac, Synaptogenesis",
author = "Huaye Zhang and Webb, {Donna J.} and Hannelore Asmussen and Shuang Niu and Horwitz, {Alan F.}",
year = "2005",
month = "3",
day = "30",
doi = "10.1523/JNEUROSCI.3553-04.2005",
language = "English (US)",
volume = "25",
pages = "3379--3388",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "13",

}

TY - JOUR

T1 - A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC

AU - Zhang, Huaye

AU - Webb, Donna J.

AU - Asmussen, Hannelore

AU - Niu, Shuang

AU - Horwitz, Alan F.

PY - 2005/3/30

Y1 - 2005/3/30

N2 - Three of seven recently identified genes mutated in nonsyndromic mental retardation are involved in Rho family signaling. Two of the gene products, α-p-21-activated kinase (PAK) interacting exchange factor (αPIX) and PAK3, form a complex with the synaptic adaptor protein G-protein-coupled receptor kinase-interacting protein 1 (GIT1). Using an RNA interference approach, we show that GIT1 is critical for spine and synapse formation. We also show that Rac is locally activated in dendritic spines using fluorescence resonance energy transfer. This local activation of Rac is regulated by PIX, a Rac guanine nucleotide exchange factor. PAK1 and PAK3 serve as downstream effectors of Rac in regulating spine and synapse formation. Active PAK promotes the formation of spines and dendritic protrusions, which correlates with an increase in the number of excitatory synapses. These effects are dependent on the kinase activity of PAK, and PAK functions through phosphorylating myosin II regulatory light chain (MLC). Activated MLC causes an increase in dendritic spine and synapse formation, whereas inhibiting myosin ATPase activity results in decreased spine and synapse formation. Finally, both activated PAK and activated MLC can rescue the defects of GIT1 knockdown, suggesting that PAK and MLC are downstream of GIT1 in regulating spine and synapse formation. Our results point to a signaling complex, consisting of GIT1, PIX, Rac, and PAK, that plays an essential role in the regulation of dendritic spine and synapse formation and provides a potential mechanism by which αPIX and PAK3 mutations affect cognitive functions in mental retardation.

AB - Three of seven recently identified genes mutated in nonsyndromic mental retardation are involved in Rho family signaling. Two of the gene products, α-p-21-activated kinase (PAK) interacting exchange factor (αPIX) and PAK3, form a complex with the synaptic adaptor protein G-protein-coupled receptor kinase-interacting protein 1 (GIT1). Using an RNA interference approach, we show that GIT1 is critical for spine and synapse formation. We also show that Rac is locally activated in dendritic spines using fluorescence resonance energy transfer. This local activation of Rac is regulated by PIX, a Rac guanine nucleotide exchange factor. PAK1 and PAK3 serve as downstream effectors of Rac in regulating spine and synapse formation. Active PAK promotes the formation of spines and dendritic protrusions, which correlates with an increase in the number of excitatory synapses. These effects are dependent on the kinase activity of PAK, and PAK functions through phosphorylating myosin II regulatory light chain (MLC). Activated MLC causes an increase in dendritic spine and synapse formation, whereas inhibiting myosin ATPase activity results in decreased spine and synapse formation. Finally, both activated PAK and activated MLC can rescue the defects of GIT1 knockdown, suggesting that PAK and MLC are downstream of GIT1 in regulating spine and synapse formation. Our results point to a signaling complex, consisting of GIT1, PIX, Rac, and PAK, that plays an essential role in the regulation of dendritic spine and synapse formation and provides a potential mechanism by which αPIX and PAK3 mutations affect cognitive functions in mental retardation.

KW - Cytoskeleton

KW - Dendritic spines

KW - GIT1

KW - MLC

KW - PAK

KW - PIX

KW - Rac

KW - Synaptogenesis

UR - http://www.scopus.com/inward/record.url?scp=16344390935&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16344390935&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3553-04.2005

DO - 10.1523/JNEUROSCI.3553-04.2005

M3 - Article

C2 - 15800193

AN - SCOPUS:16344390935

VL - 25

SP - 3379

EP - 3388

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 13

ER -