The transcription factor Foxc1a in zebrafish directly regulates expression of nkx2.5, encoding a transcriptional regulator of cardiac progenitor cells

Abstract

Cardiogenesis is a tightly controlled biological process required for formation of a functional heart. The transcription factor Foxc1 not only plays a crucial role in outflow tract development in mice, but is also involved in cardiac structure formation and normal function in humans. However, the molecular mechanisms by which Foxc1 controls cardiac development remain poorly understood. Previously, we reported that zebrafish embryos deficient in , an ortholog of mammalian, display pericardial edemas and die 9-10 days postfertilization. To further investigate Foxc1a's role in zebrafish cardiogenesis and identify its downstream target genes during early heart development, we comprehensively analyzed the cardiovascular phenotype of -null zebrafish embryos. Our results confirmed that-null mutants exhibit disrupted cardiac morphology, structure, and function. Performing transcriptome analysis on the mutants, we found that the expression of the cardiac progenitor marker gene was significantly decreased, but the expression of germ layer-patterning genes was unaffected. Dual-fluorescence hybridization assays revealed that and are co-expressed in the anterior lateral plate mesoderm at the somite stage. Chromatin immunoprecipitation and promoter truncation assays disclosed that Foxc1a regulates expression via direct binding to two noncanonical binding sites in the proximal promoter. Moreover, functional rescue experiments revealed that developmental stage-specific overexpression partially rescues the cardiac defects of the -null embryos. Taken together, our results indicate that during zebrafish cardiogenesis, Foxc1a is active directly upstream of.

Expression of smooth muscle-like effectors and core cardiomyocyte regulators in the contractile papillae of Ciona

“…Although we note that it is not clear whether all these factors are present as proteins in the ACCs and whether or not they bind DNA as a single complex, it is not clear they do so in vertebrates either. For instance, FoxC1 and FoxC2 are expressed early in vertebrate cardiac development and are required for downstream expression of other CoRC genes like Nkx2.5 and Mef2c [ 57 , 119 ], suggesting some of these factors might not function as a literal protein complex but more like a conserved subset of a gene regulatory network. Additionally, GATA mRNA expression is downregulated in Nkx2.5+ cardiomyocyte progenitors [ 53 ], also indicating that CoRC gene expression in vertebrates may be just as dynamic as we see in the ACC lineage.…”

Valves Are a Conserved Feature of the Zebrafish Lymphatic System

“…Both prox1a and nfatc1 mutants exhibit relatively normal circulatory function with only a mild decrease in vascular volume in the cranial vessels ( Figures S7A and S7B). By contrast, embryos bearing a nonsense mutation in foxc1a that causes a premature truncation within the Forkhead domain (foxc1a p162 ) display severe pericardial edema and near complete loss of circulatory function by 48 hpf (Yue et al, 2018), likely due to an early failure to connect the outflow tract to the first aortic arch ( Figures S7C-S7E). These early and severe circulatory defects preclude a straightforward analysis of lymphatic valve development.…”

Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects

“…However, ethanol-induced gene expression change for sox2 was higher (and possibly playing a more significant role) than foxc1a, foxa2, elf3 and cdx4. Foxc1a plays crucial role in somitogenesis, cardiovascular and retina development during embryogenesis [43][44][45][46][47][48] . Foxa transcription factors are essential for developmental of dorsal axis structures including prechordal plate, notochord, hypochord, and floor plate [49][50][51] .…”