Transcriptome analysis of mouse and human sinoatrial node cells reveals a conserved genetic program

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Cardiology

Background:

• The heart's contraction rate depends on the sinoatrial node (SAN), a complex structure with diverse cell types.
• Tbx3-expressing (Tbx3+) cells are critical pacemaker cells within the SAN.

Purpose of the Study:

• To characterize Tbx3+ cells using a Tbx3+/Venus knock-in mouse model.
• To identify the gene expression programs governing SAN development and function.
• To investigate the conservation of these programs between mouse and human SANs.

Main Methods:

• Isolation and electrophysiological characterization of Tbx3+/Venus labeled cells.
• Transcriptome analysis of FACS-purified Tbx3+ SAN cells and other cardiac cells from fetal mice.
• Transcriptome analysis of human fetal SAN regions and right atrium.

Main Results:

• Venus-labeled cells confirmed as genuine Tbx3+ pacemaker cells with developmental electrophysiological properties.
• A conserved gene program, including transcription factors, BMP signaling, and Smoc2, was identified in the mouse SAN.
• Disruption of Smoc2 did not impact mouse heart rhythm.
• A conserved gene program, including TBX3, SHOX2, ISL1, HOX genes, BMP, and NOTCH signaling, was found in both human and mouse SANs.

Conclusions:

• The Tbx3+/Venus allele is a valuable tool for studying SAN development and function.
• A conserved gene program underlies the development and function of the sinoatrial node region in mammals.
• Key molecular pathways and transcription factors are conserved in mammalian SAN development.