CYCLINS AND CYCLIN-DEPENDENT KINASES DURING CARDIAC DEVELOPMENT

The molecular mechanisms that regulate the cardiomyocyte cell cycle an d its terminal differentiation remain largely unknown. To determine wh ich cyclins or cyclin dependent kinases (CDKs) are important for cardi omyocyte proliferation, we examined the expression of cyclins and CDKs during normal cardiac development. All cyclins and CDKs were highly e xpressed 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 th e mRNAs of cyclins D1, D2, D3, and E (G1 and S phase cyclins) were obs erved during all stages of development, the proteins of cyclins D1, D3 , and E were observed in hearts at the young growth stage, although th e levels decreased differently. Reverse transcriptase-polymerase chain reaction (RT-PCR) using specific cyclin B and D3 primers revealed tha t cyclins B and D3 originated from cardiomyocytes and noncardiomyocyte s. The CDKs (cdc2, CDK2, and CDK4) were highly expressed during embryo nic cardiac development and maintained almost constant levels during n eonatal periods. However, they were expressed at very low levels at th e young and adult stages. The pattern of proliferating cell nuclear an tigen (PCNA) expression during cardiac development was similar to the expression of CDKs. These findings suggest that all cyclins and CDKs a re involved in the cardiac cell cycle, and that marked and rapid reduc tion of mitotic cyclins may be associated with the withdrawal of the c ardiac cell cycle after birth.