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Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a
1Department of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kuhonji 4-24-1, Kumamoto 862-0976, Japan.
Abstract:
A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cyclic AMP response element-binding protein (CREB)-binding protein (CBP) gene. Heterozygous CBP-deficient mice, which had truncated CBP protein (residues 1-1084) containing the CREB-binding domain (residues 462-661), showed clinical features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%). Truncated CBP is considered to have been acting during development as a dominant-negative inhibitor to lead to the phenotypes of RTS in mice. Our studies with step-through-type passive avoidance tests and with fear conditioning test showed that mice were deficient in long-term memory (LTM). In contrast, short-term memory (STM) appeared to be normal. These results implicate a crucial role for CBP in mammalian LTM. Our CBP +/- mice would be an excellent model for the study of the role of CBP in development and memory storage mechanisms.
Insights
Researchers developed a mouse model for Rubinstein-Taybi syndrome (RTS) by mutating the cyclic AMP response element-binding protein (CREB)-binding protein (CBP) gene. These mice exhibit RTS features and impaired long-term memory (LTM), highlighting CBP's role in memory.
Area of Science:
- Genetics and Developmental Biology
- Neuroscience
Background:
- Rubinstein-Taybi syndrome (RTS) is a rare genetic disorder characterized by developmental abnormalities.
- The cyclic AMP response element-binding protein (CREB)-binding protein (CBP) is crucial for gene transcription and cellular processes.
- Previous studies suggest a role for CBP in cognitive functions, but its specific involvement in RTS pathogenesis and memory remains unclear.
Purpose of the Study:
- To generate and characterize a mouse model for Rubinstein-Taybi syndrome (RTS) using a genetic mutation in the CBP gene.
- To investigate the role of CBP deficiency in the development of RTS-like phenotypes.
- To assess the impact of CBP deficiency on learning and memory processes, particularly long-term memory (LTM).
Main Methods:
- An insertional mutation was introduced into the CBP gene in mice to create heterozygous CBP-deficient (CBP +/-) mice.
- Phenotypic analysis included assessment of growth, skeletal maturation, craniofacial development, cardiac, and skeletal abnormalities.
- Behavioral tests, including passive avoidance and fear conditioning, were used to evaluate short-term memory (STM) and LTM.
Main Results:
- CBP +/- mice exhibited key clinical features of RTS, including growth retardation, delayed osseous maturation, hypoplastic maxilla, and skeletal abnormalities.
- The truncated CBP protein in these mice is hypothesized to act as a dominant-negative inhibitor during development.
- Mice demonstrated significant deficits in LTM but showed normal STM, implicating CBP in LTM formation.
Conclusions:
- The generated CBP +/- mouse model effectively recapitulates the developmental and cognitive phenotypes of RTS.
- CBP plays a critical role in mammalian LTM formation and consolidation.
- This mouse model provides a valuable tool for further research into CBP function in development and memory mechanisms.