Creld1 regulates myocardial development and function

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• Cysteine-Rich with EGF-Like Domains 1 (CRELD1) is a known risk gene for human atrioventricular septal defects.
• Previous studies in mouse models highlighted CRELD1's essential role in embryonic heart development, particularly septum and valve formation.
• Global CRELD1 knockout leads to embryonic lethality, preventing investigation of its later-stage functions.

Purpose of the Study:

• To investigate the cell type-specific functions of CRELD1 during peri- and postnatal heart development.
• To elucidate the role of CRELD1 in endocardial and myocardial compartments.
• To understand the molecular mechanisms underlying CRELD1's contribution to cardiac maturation and function.

Main Methods:

• Generation of conditional CRELD1 knockout mouse models: endocardial-specific (KO ^Tie2) and myocardial-specific (KO ^MyHC).
• Comprehensive cardiac phenotyping, including histology and immunohistochemistry.
• Molecular analyses using RNA-sequencing and flow cytometry to assess signaling pathways and cellular changes.

Main Results:

• CRELD1 function within the endocardium is dispensable for heart development.
• Myocardial deletion of CRELD1 (KO ^MyHC) results in significant extracellular matrix remodeling and impaired trabeculation.
• KO ^MyHC mice exhibit myocardial hypoplasia, leading to early postnatal lethality, mediated by Notch1 signaling pathway modulation.

Conclusions:

• CRELD1 plays a dual role in heart development, essential for early septa/valve formation and later cardiac maturation.
• Myocardial CRELD1 is critical for postnatal cardiac development, function, and survival.
• These findings underscore CRELD1's vital importance in mammalian heart development and function throughout different life stages.