Cardiac arrhythmias stemming from abnormal sinoatrial node (SAN) function can lead to sudden death. Developing a biological pacemaker device for treating sick sinus syndrome (SSS) could offer a potential cure. Understanding SAN differentiation is crucial, yet its regulatory mechanism remains unclear. We reanalyzed published RNA-seq data and identified Odz4 as a SAN-specific candidate. In situ hybridization revealed Odz4 expression in the cardiac crescent and throughout the cardiac conduction system (CCS). To assess the role of Odz4 in CCS differentiation, we utilized a Tet-Off inducible system for its intracellular domain (ICD). Embryonic bodies (EBs) exogenously expressing Odz4-ICD exhibited an increased propensity to develop into pacemaker-like cells with enhanced automaticity and upregulated expression of SAN-specific genes. CellChat and GO analyses unveiled SAN-specific enrichment of ligand-receptor sets, especially Ptn-Ncl, and extracellular matrix components in the group exogenously expressing Odz4-ICD. Our findings underscore the significance of Odz4 in SAN development and offer fresh insights into biological pacemaker establishment.
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http://dx.doi.org/10.1002/1873-3468.15036 | DOI Listing |
FEBS Lett
October 2024
Department of Physiology and Biophysics, Hiroshima University, Japan.
J Toxicol Pathol
July 2021
Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
There are limited data on the gene expression profiles of ion channels in the sinoatrial node (SAN) of dogs and monkeys. In this study, the messenger RNA (mRNA) expression profiles of various ion channels in the SAN of naïve dogs and monkeys were examined using RNAscope hybridization and compared with those in the surrounding right atrium (RA) of each species. Regional-specific Cav1.
View Article and Find Full Text PDFCirculation
July 2021
Department of Physiology & Cell Biology (A.K., N.L., E.J.A., B.J.H., P.M.L.J., P.J.M., V.V.F.), The Ohio State University Wexner Medical Center, Columbus.
Circ Res
December 2020
Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam (V.W.W.v.E., F.M.B., K.v.D., R.A.M., V.W., C.d.G.-d.V., I.B.H., A.O.V., B.J.B., V.M.C.).
Rationale: The development and function of the pacemaker cardiomyocytes of the sinoatrial node (SAN), the leading pacemaker of the heart, are tightly controlled by a conserved network of transcription factors, including TBX3 (T-box transcription factor 3), ISL1 (ISL LIM homeobox 1), and SHOX2 (short stature homeobox 2). Yet, the regulatory DNA elements (REs) controlling target gene expression in the SAN pacemaker cells have remained undefined.
Objective: Identification of the regulatory landscape of human SAN-like pacemaker cells and functional assessment of SAN-specific REs potentially involved in pacemaker cell gene regulation.
The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability.
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