Programming the Myocardium: the Notch-Wnt Axis

Heart related deaths are the number one cause of death in the United States. While heart failure and other mechanical issues are common, arrhythmias account for the majority of these deaths. By understanding the genetic architecture that patterns the normal cardiac conduction system, we can further deepen our understanding of how arrhythmias arise and develop targeted therapies to treat this deadly class of disease. I have found that canonical Wnt signaling is necessary for development of the atrioventricular junction. Furthermore, absence of myocardial Wnt signaling leads to tricuspid atresia. Overexpression of Wnt signaling leads to development of ectopic atrioventricular junction tissue and induces delayed conduction velocity and other electrophysiological properties of nodal tissue. I have further found that Wnt signaling is downregulated by Notch signaling and this downregulation is required for Notch induced ventricular preexcitation. I have also developed a gene therapy platform for testing the role of these genes in cultured mouse and human cardiac tissue

Programming the Myocardium: the Notch-Wnt Axis

Heart related deaths are the number one cause of death in the United States. While heart failure and other mechanical issues are common, arrhythmias account for the majority of these deaths. By understanding the genetic architecture that patterns the normal cardiac conduction system, we can further deepen our understanding of how arrhythmias arise and develop targeted therapies to treat this deadly class of disease. I have found that canonical Wnt signaling is necessary for development of the atrioventricular junction. Furthermore, absence of myocardial Wnt signaling leads to tricuspid atresia. Overexpression of Wnt signaling leads to development of ectopic atrioventricular junction tissue and induces delayed conduction velocity and other electrophysiological properties of nodal tissue. I have further found that Wnt signaling is downregulated by Notch signaling and this downregulation is required for Notch induced ventricular preexcitation. I have also developed a gene therapy platform for testing the role of these genes in cultured mouse and human cardiac tissue

On Petition for a Writ of Certiorari to The United States Court of Appeals for The Eighth Circuit, Brief of Law Professors Paul F. Rothstein, et. al., Office of the President v. Office of Independent Counsel

This Court should grant review not only because this is a case of national importance and prominence, but also because the decision below is a conspicuous departure from settled principles of evidence law. The panel majority concluded that communications between government lawyers and government officials are not protected by the attorney-client privilege, at least when those communications are sought by a federal grand jury. That conclusion conflicts with the predominant common-law understanding that the attorney-client privilege applies to government entities and that where the privilege applies, it is absolute (i.e., it protects against disclosure in all types of legal and investigative proceedings). In particular, the Court of Appeals\u27 decision rests on a fundamental misunderstanding of this Court\u27s decisions in Upjohn Co. v. United States, 449 U.S. 383 (1981), and United States v. Nixon, 418 U.s. 683 (1974). Moreover, this case warrants further review because the decision below has profound implications beyond the parties to this dispute. The Court of Appeals\u27 ruling, if allowed to stand, will create widespread uncertainty among federal, state, and local officials concerning the extent to which their communications with their agency lawyers, for the purpose of seeking legal advice in the conduct of governmental affairs, are protected by the attorney-client privilege. Unless this Court grants review and resolves this uncertainty, the decision below will likely have an adverse effect on the current and future operation of not only the Office of the President of the United States, but also government at all levels. At the very least, a decision of such vast implications (as in the present case) should be made by the highest court in the land. We accordingly urge the Court to grant the petition for review

Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties

Proper patterning of the atrioventricular canal (AVC) is essential for delay of electrical impulses between atria and ventricles, and defects in AVC maturation can result in congenital heart disease. To determine the role of canonical Wnt signaling in the myocardium during AVC development. We used a novel allele of β-catenin that preserves β-catenin's cell adhesive functions but disrupts canonical Wnt signaling, allowing us to probe the effects of Wnt loss of function independently. We show that the loss of canonical Wnt signaling in the myocardium results in tricuspid atresia with hypoplastic right ventricle associated with the loss of AVC myocardium. In contrast, ectopic activation of Wnt signaling was sufficient to induce formation of ectopic AV junction-like tissue as assessed by morphology, gene expression, and electrophysiological criteria. Aberrant AVC development can lead to ventricular pre-excitation, a characteristic feature of Wolff-Parkinson-White syndrome. We demonstrate that postnatal activation of Notch signaling downregulates canonical Wnt targets within the AV junction. Stabilization of β-catenin protein levels can rescue Notch-mediated ventricular pre-excitation and dysregulated ion channel gene expression. Our data demonstrate that myocardial canonical Wnt signaling is an important regulator of AVC maturation and electric programming upstream of Tbx3. Our data further suggest that ventricular pre-excitation may require both morphological patterning defects, as well as myocardial lineage reprogramming, to allow robust conduction across accessory pathway tissu