Cardiovascular developmental disorders are the leading cause of congenital birth defects in the United States and remain a persistent public health issue. While much progress has been made in identifying the genetic and molecular mechanisms that control heart development and function, many questions remain unanswered. The Myocardin-Related Transcription Factors A and B (MRTF-A and MRTF-B) are highly homologous proteins that interact with Serum Response Factor (SRF) and bind CArG boxes found in the control regions of genes that regulate actin dynamics and muscle contraction, among other processes. While mice lacking SRF in cardiac tissue are embryonic lethal, mice that are mutant for either MRTF-A or MRTF-B display no major cardiac defects. We hypothesized that the failure to observe a cardiac phenotype in the single MRTF-A or MRTF-B mice was due to their high homology and potential redundancy. To address this question, we generated mice that lack MRTF-A and MRTF-B in cardiomyocytes, allowing us to interrogate the role of the MRTFs in cardiac development and function. We have observed that the majority of cardiac-specific MRTF-A/MRTF-B null mice die at postnatal day 1 due to presumed defects in cardiac development and/or function. We will use a combination of techniques including immunohistochemistry, electron microscopy, echocardiography, and quantitative real-time polymerase chain reaction to identify the defects in heart development that lead to the observed postnatal lethality. Subsequently, using both unbiased and targeted approaches, we will identify the genetic and molecular mechanisms that underlie our observations. Together, the experiments we propose here will offer new insight into the genetic regulators of heart development and function and the role that the Myocardin-Related Transcription Factors play in this process. Our findings also have the potential to yield insight into the causes of cardiac birt defects in infants, a leading cause of infant mortality.
Cardiovascular abnormalities remain the most common type of birth defect in the United States. Our goal is to identify novel genetic and molecular regulator of cardiac development. By understanding the factors controlling heart development and function, we can gain insight into potential causes of birth defects and identify genetic factors contributing to these disorders.
|Carroll, Kelli J; Olson, Eric N (2017) Considerations for Cardiac CRISPR. Circ Res 121:1111-1112|