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Published on: July 27, 2022
Crim1 has cell-autonomous and paracrine roles during embryonic heart development
Swati Iyer1, Fang Yu Chou1, Richard Wang1
1School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, Australia.
Insights
Crim1 is essential for embryonic heart development, regulating epicardium-derived cells and myocardial growth. Loss of Crim1 causes congenital heart defects and impaired cardiac development.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- The epicardium is crucial for embryonic heart development, providing cells and signals for myocardial growth.
- Crim1, a transmembrane protein in epicardial cells, has an unknown role in heart development.
Purpose of the Study:
- To investigate the function of Crim1 in cardiogenesis and its role in epicardium-derived cell behavior.
- To determine the impact of Crim1 deficiency on embryonic heart development and congenital heart defects.
Main Methods:
- Utilized knockout mouse models to study Crim1 function in vivo.
- Analyzed epicardial defects, myocardial development, cell proliferation, apoptosis, and differentiation in Crim1-deficient hearts.
- Examined downstream signaling pathways including phospho-SMAD2 and phospho-ERK1/2.
Main Results:
- Loss of Crim1 leads to congenital heart defects, including epicardial abnormalities and hypoplastic myocardium.
- Crim1 deficiency increases epicardial epithelial-to-mesenchymal transition, myocardial invasion, and epicardial cell migration.
- Crim1 is necessary for epicardium-derived cell proliferation, differentiation into cardiac fibroblasts, and regulation of cardiomyocyte proliferation and apoptosis.
Conclusions:
- Crim1 is essential for both cell-autonomous and paracrine functions in heart development.
- Crim1 plays a critical role in regulating epicardium-derived trophic factors and cardiomyocyte homeostasis.
- Crim1 may modulate TGFβ signaling pathways during cardiac development.
Abstract:
The epicardium has a critical role during embryonic development, contributing epicardium-derived lineages to the heart, as well as providing regulatory and trophic signals necessary for myocardial development. Crim1 is a unique trans-membrane protein expressed by epicardial and epicardially-derived cells but its role in cardiogenesis is unknown. Using knockout mouse models, we observe that loss of Crim1 leads to congenital heart defects including epicardial defects and hypoplastic ventricular compact myocardium. Epicardium-restricted deletion of Crim1 results in increased epithelial-to-mesenchymal transition and invasion of the myocardium in vivo, and an increased migration of primary epicardial cells. Furthermore, Crim1 appears to be necessary for the proliferation of epicardium-derived cells (EPDCs) and for their subsequent differentiation into cardiac fibroblasts. It is also required for normal levels of cardiomyocyte proliferation and apoptosis, consistent with a role in regulating epicardium-derived trophic factors that act on the myocardium. Mechanistically, Crim1 may also modulate key developmentally expressed growth factors such as TGFβs, as changes in the downstream effectors phospho-SMAD2 and phospho-ERK1/2 are observed in the absence of Crim1. Collectively, our data demonstrates that Crim1 is essential for cell-autonomous and paracrine aspects of heart development.
