Molecular Cardiology

As prototypical cellular motor proteins, most myosins convert the energy of ATP into movement. Contractile muscle myosin II proteins participate in the beating of the heart and movement of the body, while non-muscle myosin IIs play an integral role in cellular movement, shape regulation, and division. Dr. Adelstein’s laboratory is focused on the role of non-muscle myosin II (NMII) in development and disease.

Three genes—MYH9, MYH10, and MYH14—encode the heavy chains of the individual NMII proteins: NMII-A, NMII-B, and NMII-C, which are composed of both heavy and light chains. Dr. Adelstein and colleagues first described the phosphorylation and regulation of NMII ATPase activity in a seminal Nature paper in 1975. His laboratory has subsequently shifted its emphasis from predominantly biochemical approaches to transgenic mouse studies. By systematically ablating each of the heavy chain genes alone and in combination, Dr. Adelstein and his colleagues have discovered critical roles for NMII-A and NMII-B in early embryonic development, including a requirement for NMII-A in the visceral endoderm and placenta and for NMII-B in the normal development of the heart and brain. A combined KO of NM II-B and II-C in cardiac myocytes results in defects in karyokinesis.  

It has been known for several years that single amino acid mutations in MYH9 lead to a human disease syndrome called MYH9-RD that includes abnormalities of the kidneys, platelets, lens of the eye, and the inner ear. Dr. Adelstein and his colleagues have generated transgenic mice that duplicate the human mutations and recapitulate the major features of the human disease. They use these animal models to study the molecular and cellular mechanisms that give rise to the specific defects.

Dr. Adelstein and colleagues first studied mutations in MYH10 that lead to strikingly abnormal heart development in the mouse—the heart develops outside of the body (ectopia cordis) due to a failure of ventral wall closure. In rare instances, children are born with and surgically treated for the same unusual defect. Coming full circle, Dr. Adelstein’s laboratory in collaboration with the University of Washington is carrying out whole exomic  sequencing on probands with the diagnosis of Pentalogy of Cantrell and their parents.

In vertebrates two of the paralogs (NM IIB and IIC) undergo alternative splicing. Studies of the mechanism responsible for splicing in the brain show that the Rbfox family of RNA binding proteins plays an essential role in NM IIB splice regulation. Characterization of these proteins demonstrates that they are required for neuronal differentiation during spinal cord development by regulating pre-mRNA splicing of Numb, a signaling adaptor protein. Recent work in this lab has shown a novel function for Rbfox in microRNA biogenesis.

Our present research projects include: the role of NM IIA in spermatogenesis; the function of NMIIs in cardiac development; using whole exomic sequencing to study causative genes for Pentalogy of Cantrell; understanding the role of NM IIA in squamous cell carcinoma; NMII and mechanotransduction; and studying the functions of the Rbfox  family of proteins.