Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis

Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55(-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55(-/-) embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3β/β-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3β. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.Behnam Rashidieh, Belal Shohayeb, Amanda Louise Bain, Patrick R.J. Fortuna, Debottam Sinha, Andrew Burgess, Richard Mills, Rachael C. Adams, J. Alejandro Lopez, Peter Blumbergs, John Finnie, Murugan Kalimutho, Michael Piper, James Edward Hudson, Dominic C.H. Ng, Kum Kum Khanna

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.Richard J. Mills, Sean J. Humphrey, Patrick R.J. Fortuna, Mary Lor, Simon R. Foster, Gregory A. Quaife-Ryan, Rebecca L. Johnston, Troy Dumenil, Cameron Bishop, Rajeev Rudraraju, Daniel J. Rawle, Thuy Le, Wei Zhao, Leo Lee, Charley Mackenzie-Kludas, Neda R. Mehdiabadi, Christopher Halliday, Dean Gilham, Li Fu, Stephen J. Nicholls, Jan Johansson, Michael Sweeney, Norman C.W. Wong, Ewelina Kulikowski, Kamil A. Sokolowski, Brian W.C. Tse, Lynn Devilee, Holly K. Voges, Liam T. Reynolds, Sophie Krumeich, Ellen Mathieson, Dad Abu-Bonsrah, Kathy Karavendzas, Brendan Griffen, Drew Titmarsh, David A. Elliott, James McMahon, Andreas Suhrbier, Kanta Subbarao, Enzo R. Porrello, Mark J. Smyth, Christian R. Engwerda, Kelli P.A. MacDonald, Tobias Bald, David E. James, and James E. Hudso