Novo Nordisk Fonden - Biovidenskab og Basal Biomedicin - Molecular signaling and transcriptional networks regulating heart development

Adequate expression of CK2α, the most abundant of the two catalytic isoforms of protein kinase CK2, is essential for proper cardiac development as its absence leads to early embryonic death due to major structural defects in the heart. To date, it remains largely unknown what fundamental cellular processes are responsible for the observed embryonic lethality. We have recently obtained compelling in vivo and in vitro evidence showing that lack of CK2α results in significantly reduced expression levels of MCM helicases that are essential components of the DNA replication machinery. Preliminary results have shown that CK2 targets for phosphorylation MEF2C transcription factor which is a key regulator of cardiomyogenesis in animal models controlling the expression of a
number of cardiogenic factors.
In this project, i) we will investigate the unique targets and pathways perturbed in cardiac cells lacking CK2α leading to delayed G1/S cell cycle transition and reduced cell proliferation, ii) we will determine whether decreased number of origins of replication resulting from lowered expression levels of DNA helicases, increases the frequency of DNA breaks and iii) we will demonstrate that CK2α regulates the in vivo activity of MEF2C which has been recently linked to transcriptional regulation of cardiac helicases expression. Mouse embryo
cardiomyocytes will be employed in adenovirus-based rescue experiments for investigating whether MEF2C phospho-mimetic mutant rescues the molecular and cellular defects observed following CK2α deletion. The proposed investigation will analyze how CK2α and MEF2C converge to regulate cardiac cells proliferation and in a broader way, will provide novel insights into molecular mechanisms controlling cardiogenesis possibly offering new tools for therapeutic applications.