Creld1 regulates myocardial development and function

Abstract

CRELD1 (Cysteine-Rich with EGF-Like Domains 1) is a risk gene for non-syndromic atrioventricular septal defects in human patients. In a mouse model, Creld1 has been shown to be essential for heart development, particularly in septum and valve formation. However, due to the embryonic lethality of global Creld1 knockout (KO) mice, its cell type-specific function during peri-and postnatal stages remains unknown.Here, we generated conditional Creld1 KO mice lacking Creld1 either in the endocardium (KO Tie2 ) or the myocardium (KO MyHC ). Using a combination of cardiac phenotyping, histology, immunohistochemistry, RNAsequencing, and flow cytometry, we demonstrate that Creld1 function in the endocardium is dispensable for heart development. Lack of myocardial Creld1 causes extracellular matrix remodeling and trabeculation defects by modulation of the Notch1 signaling pathway. Hence, KO MyHC mice die early postnatally due to myocardial hypoplasia.Our results reveal that Creld1 not only controls the formation of septa and valves at an early stage during heart development, but also cardiac maturation and function at a later stage. These findings underline the central role of Creld1 in mammalian heart development and function.

Polymorphisms of CRELD1 and DNAJC30 and their relationship with chicken carcass traits

“…Cysteine rich with epidermal growth factor like domains 1 ( CRELD1 ) is a multifunctional gene that mostly plays important roles in myocardial development ( Beckert et al, 2021 ) and immune system homeostasis ( Bonaguro et al, 2020 ). Most human fetal and adult tissues express CRELD1 and the gene expression in skeletal muscle and adult heart has a higher level ( Rupp et al, 2002 ).…”

The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity

“…Proteins of the Creld family [cysteine-rich with epithelial growth factor (EGF)–like domains] are ER proteins that have been reported to regulate ER stress response and untranslated protein response ( 23 , 24 ). CRELD1 is a risk gene for atrioventricular septal defects, and murine CRELD1 is required during heart development ( 25 ). A recent study links human CRELD1 to T cell survival ( 26 ).…”

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis

“…1,4 We previously characterized the function of Creld1 as being essential for heart development and immune cell function in mice. [4][5][6] In contrast, Creld2 is localized predominantly within the endoplasmic reticulum (ER) and can be secreted. 3,7,8 Indeed, Creld2 has been suggested as a biomarker in human body fluids for molecular phenotyping of pathophysiologies such as kidney disease 9 and prosthetic joint infections.…”

“…Creld1 is found anchored in the plasma membrane facing the extracellular matrix 1,4 . We previously characterized the function of Creld1 as being essential for heart development and immune cell function in mice 4–6 . In contrast, Creld2 is localized predominantly within the endoplasmic reticulum (ER) and can be secreted 3,7,8 .…”