Abstract
In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including α-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX(ΔE2) mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX(ΔE2) mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX(ΔE2) mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX(ΔE2) mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX(ΔE2) mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX(ΔE2) mice may contribute to mental retardation syndromes seen in human patients.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptation, Ocular / genetics
-
Analysis of Variance
-
Animals
-
Animals, Newborn
-
Astrocytes / metabolism
-
Astrocytes / pathology
-
Benzylamines / pharmacology
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
-
Cell Count / methods
-
Cells, Cultured
-
Cognition Disorders / genetics
-
Conditioning, Classical / drug effects
-
Conditioning, Classical / physiology
-
DNA Helicases / genetics*
-
Dendritic Spines / metabolism
-
Dendritic Spines / pathology*
-
Dendritic Spines / ultrastructure
-
Disease Models, Animal
-
Exons / genetics
-
Exploratory Behavior / drug effects
-
Exploratory Behavior / physiology
-
Fear / physiology
-
Gene Expression Regulation / drug effects
-
Gene Expression Regulation / genetics*
-
Green Fluorescent Proteins / genetics
-
Guanine Nucleotide Exchange Factors / metabolism
-
Humans
-
Immunoprecipitation
-
Isoquinolines
-
Learning Disabilities / genetics
-
Maze Learning / drug effects
-
Maze Learning / physiology
-
Mice
-
Mice, Transgenic
-
Motor Activity / genetics
-
Mutation / genetics*
-
Neurons / ultrastructure
-
Nuclear Proteins / genetics*
-
Phosphopyruvate Hydratase / metabolism
-
Phosphorylation / genetics
-
Prefrontal Cortex / enzymology*
-
Prefrontal Cortex / pathology
-
Protein Kinase Inhibitors / pharmacology
-
Protein Phosphatase 1 / metabolism
-
Protein Phosphatase 2 / metabolism
-
RNA, Messenger / metabolism
-
Sulfonamides / pharmacology
-
T-Lymphoma Invasion and Metastasis-inducing Protein 1
-
X-linked Nuclear Protein
Substances
-
Benzylamines
-
Guanine Nucleotide Exchange Factors
-
Isoquinolines
-
KALRN protein, mouse
-
Nuclear Proteins
-
Protein Kinase Inhibitors
-
RNA, Messenger
-
Sulfonamides
-
T-Lymphoma Invasion and Metastasis-inducing Protein 1
-
Tiam1 protein, mouse
-
KN 93
-
Green Fluorescent Proteins
-
lucifer yellow
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2
-
Protein Phosphatase 1
-
Protein Phosphatase 2
-
DNA Helicases
-
ATRX protein, human
-
X-linked Nuclear Protein
-
Phosphopyruvate Hydratase