Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Regenerative Medicine

Background:

• Cardiac ventricles generate contractile force, with trabeculae forming early myocardial projections.
• The formation and maturation of trabeculae into adult ventricles are critical for heart function.
• Neuregulin-1 (Nrg1) signaling is essential for trabeculation, but its precise role and mechanisms remain unclear.

Purpose of the Study:

• To investigate the functions and downstream mechanisms of Nrg1 signaling in ventricular chamber development.
• To understand how Nrg1 regulates cardiomyocyte cell division, migration, and trabeculation.
• To identify key molecular players in the Nrg1 signaling pathway during heart development.

Main Methods:

• Cardiac-specific inactivation and overexpression of Nrg1 in mouse models.
• Confocal imaging, transcriptomics, and biochemical analyses.
• Analysis of signaling pathways including ErbB2, Erk, and Yap1.

Main Results:

• Endocardial Nrg1 signaling to myocardial ErbB2 activates Erk, promoting cardiomyocyte division and trabeculae formation.
• Nrg1 regulates cardiomyocyte migration, adhesion, and cell cycle progression via an epithelial-to-mesenchymal transition-like process.
• Aberrant Nrg1 levels disrupt trabecular patterning and sarcomere organization, with Yap1 identified as a downstream effector.
• Nrg1 influences Erk activation and Yap1 localization during trabeculation.

Conclusions:

• The Nrg1-ErbB2/ErbB4-Erk axis is a critical regulator of cardiomyocyte cell cycle progression and migration.
• Nrg1 signaling is essential for proper ventricular wall maturation and trabecular patterning.
• Understanding this pathway offers insights for regenerative medicine approaches to cardiac repair.