Novo Nordisk Foundation - 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.