Functional patterning of the developing myocardium by the non-canonical Wnt/L-Type Ca2+-channel pathway.

• Applicant: Professorin Dr. Daniela Panakova
• Subject Area: Anatomy and Physiology ; Cardiology, Angiology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280799826

Final Report Abstract

We have fulfilled the main objective of the proposal, which was to identify the molecular mechanisms by which Wnt11 signaling attenuates the LTCC. The novel identified signaling Wnt11/AKAP2/PKA axis has major implications for cardiac muscle physiology. This axis attenuates the LTCC conductance, as observed by changes in intracellular calcium transient amplitudes and percentage of active LTCC-RyR couplons. While the cellular functions of AKAP2 are not fully characterized, we could show that the lack of akap2 affected both heart morphology and electrical coupling. These data and prior evidence demonstrating dysregulated Wnt signaling and PKA-AKAP2 in different forms of cardiomyopathies, imply potential links between Wnt11/AKAP2/PKA and human heart muscle diseases or arrhythmias. It is also plausible to hypothesize that Wnt11/AKAP2/PKA axis with its regulation of LTCC conductance may be also implicated in cardiomyocyte differentiation as LTCC has been identified as a target in differentiation of the induced pluripotent stem cells (iPS) to cardiomyocytes. There also exists some evidence from work in stem cells suggesting a complex role for the Wnt11/AKAP2/PKA axis in integration of electrical and mechanical inputs. Modulation of electrical signals through Wnt11/AKAP2/LTCC signaling might therefore be important to explore in the context of stem cell differentiation in the future.

Publications

• (2018). Continuous addition of progenitors forms the cardiac ventricle in zebrafish. Nat Commun 9, 2001
  Felker, A., Prummel, K.D., Merks, A.M., Mickoleit, M., Brombacher, E.C., Huisken, J., Panáková, D., and Mosimann, C.
  
• (2018). Planar cell polarity signalling coordinates heart tube remodelling through tissue-scale polarisation of actomyosin activity. Nat Commun 9, 2161
  Merks, A.M., Swinarski, M., Meyer, A.M., Müller, N.V., Özcan, I., Donat, S., Burger, A., Gilbert, S., Mosimann, C., Abdelilah-Seyfried, S., and Panáková, D.
  
• (2019). Advantages and Challenges of Cardiovascular and Lymphatic Studies in Zebrafish Research. Front Cell Dev Biol, 7:89
  Santoro, M., Beltrame, M., Panáková, D., Siekmann, A.F., Tiso, N., Venero Galanternik, M., Jung, H.M., and Weinstein, B.M.
  
• (2019). Wnt11/Fzd7 signaling compartmentalizes AKAP2/PKA to regulate L-type Ca2+ channel
  Csályi, K.D., Rharass, T., Schulz, M., Phan, M.H.Q., Wakula, P., Mhatre, K.N., Plotnick, D., Werdich, A.A., Zauber, H., Sury, M.D., Selbach, M., Heinzel, F.R., Klusßmann, E., and Panáková, D.