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Published on: November 22, 2024
A mouse model for Carney complex
Kurt J Griffin1, Lawrence S Kirschner, Ludmila Matyakhina
1Section on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892-1862, USA.
Abstract:
Mice with complete inactivation of the type Ialpha regulatory subunit (RIalpha) of cyclic (c) AMP-dependent protein kinase (PKA) (coded by the Prkar1a gene) die early in embryonic life. To bypass the early embryonic lethality of Prkar1a-/- mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of PPNAD, and histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. This mouse provides a useful tool for the investigation of cAMP, RIalpha, and PKA functions and confirms Prkar1a's critical role in tumorigenesis in endocrine and other tissues.
Insights
Complete inactivation of the cyclic AMP-dependent protein kinase (PKA) regulatory subunit RIalpha causes embryonic lethality. This study developed a novel mouse model to investigate PKA
Area of Science:
- Molecular biology
- Genetics
- Endocrinology
Background:
- Complete inactivation of the type Ialpha regulatory subunit (RIalpha) of cyclic (c) AMP-dependent protein kinase (PKA), encoded by the Prkar1a gene, results in early embryonic lethality in mice.
- This lethality prevents the study of RIalpha and PKA functions in later development and disease pathogenesis.
Purpose of the Study:
- To circumvent the embryonic lethality of Prkar1a knockout mice.
- To create a tool for investigating the roles of cAMP, RIalpha, and PKA in tumorigenesis.
Main Methods:
- Generation of transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS).
- The transgene was placed under the control of a tetracycline-responsive promoter to regulate its expression.
- Analysis of phenotypic outcomes in the developed transgenic mouse model.
Main Results:
- Transgenic mice exhibited thyroid follicular hyperplasia and adenomas, and adrenocortical hyperplasia, mirroring features of Primary Pigmented Nodular Adrenocortical Disease (PPNAD).
- These mice also developed histiocytic and epithelial hyperplasias, lymphomas, and various mesenchymal tumors.
- The study confirmed the critical role of Prkar1a in tumorigenesis across endocrine and other tissues.
Conclusions:
- The developed Prkar1a antisense transgenic mouse model is a valuable tool for studying cAMP, RIalpha, and PKA.
- This model confirms the essential role of Prkar1a in preventing tumor formation in endocrine and other tissues.
- The findings highlight Prkar1a's significance in regulating cell growth and differentiation.
