BMP-2 and TGFβ2 Shared Pathways Regulate Endocardial Cell Transformation

Valvular heart disease is a major cause of mortality and morbidity. Revealing the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. A key step in valve formation during heart development is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endocardial cells in the atrioventricular cushion (AVC). The type III transforming growth factor-β receptor (TGFβR3) regulates AVC endocardial cell EMT in vitro and mesenchymal cell differentiation in vivo. Little is known concerning the signaling mechanisms downstream of TGFβR3. Here we use endocardial cell EMT in vitro to determine the role of 2 well-characterized downstream TGFβ signaling pathways in TGFβR3-dependent endocardial cell EMT. Targeting of Smad4, the common mediator Smad, demonstrated that Smad signaling is required for EMT in the AVC and TGFβR3-dependent EMT stimulated by TGFβ2 or BMP-2. Although we show that Smads 1, 2, 3, and 5 are required for AVC EMT, overexpression of Smad1 or Smad3 is not sufficient to induce EMT. Consistent with the activation of the Par6/Smurf1 pathway downstream of TGFβR3, targeting ALK5, Par6, or Smurf1 significantly inhibited EMT in response to either TGFβ2 or BMP-2. The requirement for ALK5 activity, Par6, and Smurf1 for TGFβR3-dependent endocardial cell EMT is consistent with the documented role of this pathway in the dissolution of tight junctions. Taken together, our data demonstrate that TGFβR3-dependent endocardial cell EMT stimulated by either TGFβ2 or BMP-2 requires Smad4 and the activation of the Par6/Smurf1 pathway

Axion Dark Matter

Axions are well-motivated dark matter candidates with simple cosmological production mechanisms. They were originally introduced to solve the strong CP problem, but also arise in a wide range of extensions to the Standard Model. This Snowmass white paper summarizes axion phenomenology and outlines next-generation laboratory experiments proposed to detect axion dark matter. There are vibrant synergies with astrophysical searches and advances in instrumentation including quantum-enabled readout, high-Q resonators and cavities and large high-field magnets. This white paper outlines a clear roadmap to discovery, and shows that the US is well-positioned to be at the forefront of the search for axion dark matter in the coming decade.Axions are well-motivated dark matter candidates with simple cosmological production mechanisms. They were originally introduced to solve the strong CP problem, but also arise in a wide range of extensions to the Standard Model. This Snowmass white paper summarizes axion phenomenology and outlines next-generation laboratory experiments proposed to detect axion dark matter. There are vibrant synergies with astrophysical searches and advances in instrumentation including quantum-enabled readout, high-Q resonators and cavities and large high-field magnets. This white paper outlines a clear roadmap to discovery, and shows that the US is well-positioned to be at the forefront of the search for axion dark matter in the coming decade