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Published on: March 17, 2014
Axin Regulates Dendritic Spine Morphogenesis through Cdc42-Dependent Signaling
Yu Chen1, Zhuoyi Liang2, Erkang Fei2
1Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Guangdong Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China.
Abstract:
During development, scaffold proteins serve as important platforms for orchestrating signaling complexes to transduce extracellular stimuli into intracellular responses that regulate dendritic spine morphology and function. Axin ("axis inhibitor") is a key scaffold protein in canonical Wnt signaling that interacts with specific synaptic proteins. However, the cellular functions of these protein-protein interactions in dendritic spine morphology and synaptic regulation are unclear. Here, we report that Axin protein is enriched in synaptic fractions, colocalizes with the postsynaptic marker PSD-95 in cultured hippocampal neurons, and interacts with a signaling protein Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in synaptosomal fractions. Axin depletion by shRNA in cultured neurons or intact hippocampal CA1 regions significantly reduced dendritic spine density. Intriguingly, the defective dendritic spine morphogenesis in Axin-knockdown neurons could be restored by overexpression of the small Rho-GTPase Cdc42, whose activity is regulated by CaMKII. Moreover, pharmacological stabilization of Axin resulted in increased dendritic spine number and spontaneous neurotransmission, while Axin stabilization in hippocampal neurons reduced the elimination of dendritic spines. Taken together, our findings suggest that Axin promotes dendritic spine stabilization through Cdc42-dependent cytoskeletal reorganization.
Insights
Axin, a key scaffold protein, stabilizes dendritic spines by interacting with CaMKII and regulating Cdc42. This interaction is crucial for maintaining spine density and synaptic function in neurons.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Scaffold proteins are crucial for organizing signaling complexes that regulate neuronal development and function.
- Axin (axis inhibitor) is a known scaffold protein in Wnt signaling, but its role in dendritic spine morphology and synaptic regulation is not well understood.
Purpose of the Study:
- To investigate the role of Axin in dendritic spine morphology and synaptic regulation.
- To elucidate the molecular mechanisms underlying Axin's function in neurons.
Main Methods:
- Immunofluorescence and biochemical fractionation to determine Axin localization and interactions in hippocampal neurons.
- Axin depletion using shRNA and subsequent analysis of dendritic spine density.
- Overexpression of Cdc42 and pharmacological stabilization of Axin to assess effects on dendritic spines and neurotransmission.
Main Results:
- Axin protein is enriched in synaptic fractions and colocalizes with PSD-95 in hippocampal neurons.
- Axin depletion significantly reduces dendritic spine density, a phenotype rescued by Cdc42 overexpression.
- Pharmacological stabilization of Axin increases dendritic spine number and neurotransmission, while reducing spine elimination.
Conclusions:
- Axin plays a critical role in promoting dendritic spine stabilization.
- Axin exerts its function through a pathway involving CaMKII and Cdc42, leading to cytoskeletal reorganization.
- Targeting Axin may offer therapeutic potential for neurological disorders involving synaptic dysfunction.
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