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Cyclins and cyclin dependent kinases during cardiac development
1Department of Physiology, Chonbuk National University Medical School, Chonju, Korea.
Abstract:
The molecular mechanisms that regulate the cardiomyocyte cell cycle and its terminal differentiation remain largely unknown. To determine which cyclins or cyclin dependent kinases (CDKs) are important for cardiomyocyte proliferation, we examined the expression of cyclins and CDKs during normal cardiac development. All cyclins and CDKs were highly expressed during embryonic cardiac development, then they decreased at different rates after birth. The mRNAs and proteins of cyclins A and B (G2 and M phase cyclins) were found in embryonic and neonatal hearts, but were not detected in young or adult hearts. In contrast, while the mRNAs of cyclins D1, D2, D3, and E (G1 and S phase cyclins) were observed during all stages of development, the proteins of cyclins D1, D3, and E were observed in hearts at the young growth stage, although the levels decreased differently. Reverse transcriptase-polymerase chain reaction (RT-PCR) using specific cyclin B and D3 primers revealed that cyclins B and D3 originated from cardiomyocytes and noncardiomyocytes. The CDKs (cdc2, CDK2, and CDK4) were highly expressed during embryonic cardiac development and maintained almost constant levels during neonatal periods. However, they were expressed at very low levels at the young and adult stages. The pattern of proliferating cell nuclear antigen (PCNA) expression during cardiac development was similar to the expression of CDKs. These findings suggest that all cyclins and CDKs are involved in the cardiac cell cycle, and that marked and rapid reduction of mitotic cyclins may be associated with the withdrawal of the cardiac cell cycle after birth.
Insights
Cardiomyocyte cell cycle regulation is complex. Key cell cycle proteins, cyclins and cyclin-dependent kinases (CDKs), are highly expressed during embryonic development and decrease significantly after birth, suggesting their role in cardiac cell cycle withdrawal.
Area of Science:
- Cardiovascular Biology
- Cell Cycle Regulation
- Molecular Cardiology
Background:
- The molecular mechanisms governing cardiomyocyte cell cycle progression and terminal differentiation are not fully understood.
- Understanding these mechanisms is crucial for addressing cardiac development and potential regenerative therapies.
Purpose of the Study:
- To investigate the expression patterns of cyclins and cyclin-dependent kinases (CDKs) during cardiac development.
- To identify specific cyclins and CDKs critical for cardiomyocyte proliferation and cell cycle exit.
Main Methods:
- Examined the expression of various cyclins (A, B, D1, D2, D3, E) and CDKs (cdc2, CDK2, CDK4) at different developmental stages of the heart.
- Utilized reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the cellular origin of specific cyclins.
- Assessed the expression of proliferating cell nuclear antigen (PCNA) as a marker of cell proliferation.
Main Results:
- All examined cyclins and CDKs were highly expressed during embryonic cardiac development, decreasing postnatally at varying rates.
- Mitotic cyclins (A and B) were detected in embryonic and neonatal hearts but absent in adult hearts.
- G1/S phase cyclins (D1, D3, E) showed protein expression in young hearts, with differential decline. CDK and PCNA expression patterns mirrored each other, decreasing significantly in adult hearts.
- RT-PCR confirmed that cyclins B and D3 are expressed in both cardiomyocytes and non-cardiomyocytes.
Conclusions:
- Both cyclins and CDKs are integral to the cardiac cell cycle during development.
- The rapid reduction in mitotic cyclins post-birth likely contributes to the withdrawal of cardiomyocytes from the cell cycle.
- These findings provide insights into the developmental regulation of cardiac cell proliferation and differentiation.