Biology subjects

De Bono, C.

Publications and source records attributed to De Bono, C..

4 recordsLinked to original sources

bioRxiv2026

Morphogenesis of the muscular ventricular septum of the mouse heart is driven by retinoic acid signalling to myocardium

The mammalian heart is divided into four chambers by septa that isolate systemic and pulmonary circulation and are hotspots of congenital heart defects (CHD). The muscular ventricular septum develops between left and right ventricular cardiomyocytes derived from the first and second heart fields. Despite its clinical importance, mechanisms underlying development of the ventricular septum are poorly understood. Here we show that myocardial reception of retinoic acid (RA) signalling regulates formation of the compact septal core. Activation of a dominant negative RA receptor in second heart field-derived myocardium during septal morphogenesis results in a deep interventricular cleft and bifid cardiac apex. This phenotype is preceded by ectopic trabecular contributions to a RA-independent septal primordium. Molecular analysis implicates defective cardiomyocyte maturation and impaired RAC1 activation in mutant hearts. These results support an infolding and RA-dependent fusion model of septal morphogenesis, providing new insights into ventricular development and the origins of CHD.

developmental biology↗

bioRxiv2024

Multi-modal refinement of the human heart atlas during the first gestational trimester

1.Forty first-trimester human hearts were studied to lay groundwork for further studies of principles underlying congenital heart defects. We first sampled 49,227 cardiac nuclei from three fetuses at 8.6, 9.0, and 10.7 post-conceptional weeks (pcw) for single-nucleus RNA sequencing, enabling distinction of six classes comprising 21 cell types. Improved resolution led to identification of novel cardiomyocytes and minority autonomic and lymphatic endothelial transcriptomes, among others. After integration with 5-7 pcw heart single-cell RNAseq, we identified a human cardiomyofibroblast progenitor preceding diversification of cardiomyocyte and stromal lineages. Analysis of six Visium sections from two additional hearts was aided by deconvolution, and key spatial markers validated on sectioned and whole hearts in two- and three-dimensional space and over time. Altogether, anatomical-positional features including innervation, conduction and subdomains of the atrioventricular septum translate latent molecular identity into specialized cardiac functions. This atlas adds unprecedented spatial and temporal resolution to the characterization of human-specific aspects of early heart formation.

developmental biology↗

bioRxiv2022

Single cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell deployment and progression

Disruption of cardiac neural crest cells (CNCCs) results in congenital heart disease, yet we do not understand the cell fate dynamics as these cells differentiate to vascular smooth muscle cells. Here we utilized single-cell RNA-sequencing of NCCs from the pharyngeal apparatus with heart in control mouse embryos and when Tbx1, the gene for 22q11.2 deletion syndrome, is inactivated. We uncovered three dynamic transitions of pharyngeal NCCs expressing Tbx2 and Tbx3 through differentiated CNCCs expressing cardiac transcription factors with smooth muscle genes, and that these transitions are altered non-autonomously by loss of Tbx1. Further, inactivation of Tbx2 and Tbx3 in early CNCCs resulted in aortic arch branching defects due to failed smooth muscle differentiation. Loss of Tbx1 interrupted mesoderm to CNCC cell-cell communication with upregulation of BMP signaling with reduced MAPK signaling and failed dynamic transitions of CNCCs leading to disruption of aortic arch artery formation and cardiac outflow tract septation.

developmental biology↗

bioRxiv2020

Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in the murine cardiopharyngeal mesoderm

The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm (CPM) within the pharyngeal apparatus. The formation of the cardiac outflow tract and branchiomeric muscles are disrupted in patients with 22q11.2 deletion syndrome (22q11.2DS), due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we identified a multilineage primed population (MLP) within the CPM, marked by the Tbx1 lineage, which has bipotent properties to form cardiac and skeletal muscle cells. The MLPs are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of progenitors that undergo TBX1-dependent progression towards maturation. Tbx1 also regulates the balance between MLP maintenance and maturation while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance by direct regulation of MLP enriched genes and downstream pathways, partly through altering chromatin accessibility. Our study thus uncovers a new cell population and reveals novel mechanisms by which Tbx1 directs the development of the pharyngeal apparatus, which is profoundly altered in 22q11.2DS.

developmental biology↗