bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.02.24.481762

Nr2f1a maintains atrial nkx2.5 expression to repress pacemaker identity within venous atrial cardiomyocytes

Martin, K.·Ravisankar, P.·Beerens, M.·MacCrae, C.·Waxman, J.
View original source ↗Export metadata ↓

Abstract

Maintenance of cardiomyocyte identity is vital for normal heart development and function. However, our understanding of cardiomyocyte plasticity remains incomplete. Here, we show that sustained expression of the zebrafish transcription factor (TF) Nr2f1a prevents the progressive acquisition of ventricular cardiomyocyte (VC) and pacemaker cardiomyocyte (PC) identities within distinct regions of the atrium. Transcriptomic analysis of isolated atrial cardiomyocytes (ACs) from nr2f1a mutant zebrafish embryos showed increased VC marker gene expression and altered expression of core PC regulatory genes, including decreased expression of nkx2.5, a critical repressor of PC differentiation. At the arterial pole of the atrium in nr2f1a mutants, cardiomyocytes resolve to VC identity within the expanded atrioventricular canal. However, at the venous pole, there is a progressive wave of AC transdifferentiation into PCs across the atrium toward the arterial pole. Restoring Nkx2.5 is sufficient to repress PC identity in nr2f1a mutant atria and analysis of chromatin accessibility identified a Nr2f1a-dependent nkx2.5 enhancer expressed in the atrial myocardium directly adjacent to PCs, supporting that Nr2f1a limits PC differentiation within venous ACs via maintaining nkx2.5 expression. The Nr2f-dependent maintenance of AC identity within discrete atrial compartments may provide insights into the molecular etiology of concurrent structural congenital heart defects and associated arrhythmias.

Source connections

Explore related subjects

developmental biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Martin, K., Ravisankar, P., Beerens, M., MacCrae, C., Waxman, J.. 2022-02-24. Nr2f1a maintains atrial nkx2.5 expression to repress pacemaker identity within venous atrial cardiomyocytes. https://doi.org/10.1101/2022.02.24.481762

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Prenatal THC exposure alters metabolic gene expression and KEAP1 regulation in the mouse placental labyrinth

Introduction: Prenatal cannabinoid exposure may influence fetal development through changes in placental biology, yet its effects on metabolic gene regulation remain poorly understood. We examined the effects of {Delta}9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on the mouse placental labyrinth zone. Methods: Pregnant C57BL/6JRj mice received THC (5 mg/kg), CBD (5 mg/kg), or vehicle daily by intraperitoneal injection from gestational day 5 to 17.5. Targeted NanoString profiling and pathway analysis were combined with RT-qPCR and protein measurements. Results: THC exposure reduced glutaminase (Gls), Kelch-like ECH-associated protein 1 (Keap1), and FMS-like tyrosine kinase 3 (Flt3) expression (false discovery rate = 0.0904 for each). Pathway analysis identified transcriptional changes in the nine-gene arginine-metabolism set (false discovery rate = 0.0527). No genes or pathways met the significance criteria following CBD exposure. RT-qPCR confirmed lower Keap1 expression with sexes pooled and identified lower Gls and Flt3 expression in male samples. KEAP1 protein abundance increased despite lower Keap1 mRNA, while nuclear factor erythroid 2-related factor 2 localization and heme oxygenase 1 (Hmox1) expression showed no significant differences. Discussion: These findings identify amino acid metabolic gene expression and KEAP1 regulation as complementary components of the placental response to prenatal THC exposure, connecting transcriptional changes with protein regulation within the placental exchange region.

developmental biology↗
bioRxiv2026

Mutually Repressive Transcription Factors Drive Intestinal Maturation for Weaning

In mammals, rapid neonatal growth depends on specialized intestinal enterocytes that absorb nutrients from milk. These cells exhibit distinct functions, morphologies, and gene expression programs that support neonatal nutrition before transitioning to an adult state at weaning. However, the transcriptional mechanisms that establish neonatal enterocyte identity and coordinate their maturation remain poorly understood. Here we show that the transcription factors BLIMP1 and CASZ1 form a central switch in the timing of enterocyte maturation. While BLIMP1 marks and promotes neonatal enterocytes, CASZ1 is expressed in adult enterocytes and is required for the proper timing of their emergence. Genetic analysis indicates that these neonatal and adult factors are mutually repressive, forming a genetic switch underlying weaning. This regulatory mechanism also controls glucocorticoid-induced maturation, a process relevant to both normal weaning and the clinical use of corticosteroids to promote epithelial maturation in preterm infants. We show that corticosteroids act directly on the intestinal epithelium and require CASZ1 to induce maturation. Together, these findings reveal a transcriptional mechanism that coordinates intestinal epithelial identity with the changing nutritional demands of early life and mediates the response to maturation-promoting hormones.

developmental biology↗
bioRxiv2026

Functional Data Clustering of Filopodia Dynamics

Notch signaling plays a significant role in tissue patterning. During patterning of the fruit fly dorsal thorax peripheral nervous system, basal filopodia extend the spatial range of cell-cell communication, yet it is still unclear how Notch is activated in long range signaling via filopodia interaction. Filopodia undergo dynamic length changes during their lifetime, which could supply the mechanical pulling force required for notch activation. However, their dynamics are often characterized using individual scalar values such as maximum length and extension rate which could obscure more intricate dynamics. Our hypothesis is that signaling filopodia exhibit distinct and recurrent temporal patterns which can be identified by a consideration of their complete lifetime trajectories. Our work analyzes 60 filopodia trajectories at the basal surface of the fly dorsal thorax during patterning. Length profiles were smoothed using cubic B-splines and clustered by first reducing them to their dominant functional principal component followed by the application of various clustering algorithms. We found that 94.29% of the overall trajectory variation is explained by the first four functional principal components which account for variations in maximal length, extension and retraction rate, duration of stationary phase and length fluctuation frequency. Five recurrent temporal profiles (dynamic extension modes) with varying trajectory shapes and physical attributes, were identified using trimmed K-means. These findings demonstrate that whereas the major source of structural variation in filopodia profiles remains the length, extension rate and retraction rate, nontrivial combinations of these create distinct dynamic modes of extension which provide new insight into their length profiles. Our work thus offers a quantitative framework for future research connecting filopodia dynamic extension modes to productive Notch activation.

developmental biology↗