GATA4/5/6 family transcription factors are conserved determinants of cardiac versus pharyngeal mesoderm fate

Abstract

GATA4/5/6 transcription factors play essential, conserved roles in heart development. How these factors mediate the transition from multipotent mesoderm progenitors to a committed cardiac fate is unclear. To understand how GATA4/5/6 modulate cell fate decisions we labelled, isolated, and performed single-cell gene expression analysis on cells that express gata5 at pre-cardiac time points spanning gastrulation to somitogenesis. We found that most mesendoderm-derived lineages had dynamic gata5/6 expression. In the absence of Gata5/6, the population structure of mesendoderm-derived cells was dramatically altered. In addition to the expected absence of cardiac mesoderm, we observed a concomitant expansion of cranial-pharyngeal mesoderm. Functional genetic analyses in zebrafish and the invertebrate chordate Ciona, which possess a single GATA4/5/6 homolog, revealed an essential and cell-autonomous role for GATA4/5/6 in promoting cardiac and inhibiting pharyngeal mesoderm identity. Overall, the maintenance and repression of GATA4/5/6 activity plays a critical, evolutionarily conserved role in early development.

Emergence of heart and branchiomeric muscles in cardiopharyngeal mesoderm

“…Antagonistic interactions between the cardiac transcription factor nk4, homologue of Nkx2-5, and tbx1/10, homologue of Tbx1, determine cardiac or pharyngeal muscle fates [77]. These factors are coexpressed in bipotent secondary trunk ventral cells and act in part through opposing effects on expression of a GATA transcription factor that cell autonomously promotes cardiac and inhibits pharyngeal muscle identity [77,78]. Pharyngeal muscle fate potential is maintained in trunk ventral cells by Fibroblast growth factor (FGF)/ MAPK signaling [79].…”

ALDH1A2‐related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway

“…Numerous studies have uncovered a complex TBX1 gene regulatory network associated with vitamin A signaling, heart, and diaphragm development. For instance, TBX1 interacts with the transcription factor GATA4 through a conserved GATA‐TBX1 regulatory axis (Song et al, 2022). GATA4 is expressed in the heart and gonads and pathogenic variants in GATA4 are associated with cardiac and testicular anomalies in humans (Lourenço et al, 2011).…”

From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

“…In zebrafish, gata4/5/6 already contribute to early mesendoderm patterning, complicating interpretations of later phenotypes [ 54 , 150 , 156 ]. Analysis of combinatorial gata4/5/6 morphants and mutants suggests that cardiac specification depends primarily on an overall dosage of these cardiac Gata transcription factors rather than a specific gene [ 148 , 150 , 151 , 152 , 157 , 158 ]. gata6 seems to primarily regulate the differentiation of ventricular cardiomyocytes and ventricle morphogenesis through regulation of both the FHF and SHF [ 151 ].…”

“…Similarly, as described above, FGF signaling influences the timing and ultimate quantity of cells contributing to SHF-derived lineages [ 89 , 92 , 107 ], which echoes the influence of FGF signaling on CPF lineage differentiation in Ciona [ 189 , 190 ]. Recent single-cell sequencing and mutant analysis implicates gata4/5/6 in the segregation of cardiac versus pharyngeal fates, with perturbed Gata5/6 function resulting in reduced cardiac and increased pharyngeal progenitors, which mirrors the situation described for Ciona , underlining another deeply conserved regulatory mechanism of CPF patterning [ 157 ]. Overlaying the CPF concept with current models of ALPM patterning and myocardial and endocardial lineage formation provides a powerful context to understand the evolution, development, and disease context of early heart formation.…”

“…While various gene expression patterns and broader reporters have been used to map SHF progenitors within the ALPM, their specific location and dynamic migration remain to be fully determined. Single cell-based transcriptomics promises to reveal new details of SHF and earliest general heart field progenitors, as already approached in first studies [ 84 , 157 , 161 ]. Further, while broadly deemed SHF, to what extent its arterial versus venous pole-forming derivatives share a common progenitor pool in the early LPM is unclear, despite their regulatory differences [ 170 , 172 ].…”