The Matricellular Protein CCN1 Is Essential for Cardiac Development

Abstract

Abstract-The matricellular protein CCN1 (formerly named CYR61) regulates cell adhesion, migration, proliferation, survival, and differentiation through binding to integrin receptors and heparan sulfate proteoglycans. Here we show that Ccn1-null mice are impaired in cardiac valvuloseptal morphogenesis, resulting in severe atrioventricular septal defects (AVSD). Remarkably, haploinsufficiency for Ccn1 also results in delayed formation of the ventricular septum in the embryo and persistent ostium primum atrial septal defects (ASD) in Ϸ20% of adults. Mechanistically, Ccn1 is not required for epithelial-to-mesenchymal transformation or cell proliferation and differentiation in the endocardial cushion tissue. However, Ccn1 deficiency leads to precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum at embryonic day 12.5, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurs, indicating that these defects may underlie the observed AVSD. Moreover, human CCN1 maps to 1p21-p31, the chromosomal location of an AVSD susceptibility gene. Together, these results provide evidence that deficiency in matrix signaling can lead to autosomal dominant AVSD, identify Ccn1 ϩ/Ϫ mice as a genetic model for ostium primum ASD, and implicate CCN1 as a candidate gene for AVSD in humans. Key Words: apoptosis Ⅲ cardiac development Ⅲ cardiovascular disease Ⅲ integrin Ⅲ matricellular genes Ⅲ matrix metalloproteinases Ⅲ transgenic mice A trioventricular septal defect (AVSD) is a common family of genetic disorders, accounting for Ϸ7.5% of the recognized congenital heart disease (CHD) in humans. 1 During cardiac development, the endocardial cushion tissue expands through formation of the cardiac jelly, a specialized extracellular matrix (ECM) between the endocardium and myocardium, into which endocardial cells that have undergone epithelial-to-mesenchymal transformation (EMT) invade. Subsequent growth and remodeling of the cushion tissue, coupled with its fusion with the developing atrial septum and muscular interventricular septum, lead to formation of the definitive atrioventricular (AV) septa and valves. 2,3 Defects in this process are manifested in a spectrum of abnormalities with varying severities, ranging from partial forms of AVSD with ostium primum atrial septal defects (ASD) to complete forms with absence of the AV septa and lack of partitioning of the AV valve into separate mitral (left) and tricuspid (right) valves. Although AVSD is frequently associated with Down's syndrome (trisomy 21), nonsyndromic AVSD also occur. Although nonsyndromic AVSD may be a sporadic trait or the result of multifactorial inheritance, strong evidence also support the presence of susceptibility genes for AVSD that are autosomal dominant and incompletely penetrant. 4 -6 CCN1 (formerly named CYR61 [CYsteine-Rich angiogenic inducer 61; NM_001554) is a secreted, cysteine-rich protein associated with the ECM. A dynamically ...

CCN1 Mutation is Associated with Atrial Septal Defect

“…But our genetic data and pathophysiologic conclusions in combination with the Ccn1 mouse model fit together quite well and contradict this notion. Indeed, one of the strongest arguments supporting our data is the remarkable observation by Mo and Lau that haploinsuffiency for Ccn1 (heterozygous +/-mice) also resulted in delayed formation of the ventricular septum in the mouse embryo and persistent ASD in 20% of adult mice [8]. In these animals, Ccn1 haploinsuffiency caused precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurred [8].…”

“…Matricellular CCN proteins are regulatory factors involved in cell signalling participating in various crucial biological processes like cell differentiation, adhesion, and apoptosis [7]. A mouse model shed new light on the role of CCN proteins in cardiac valvuloseptal morphogenesis: Mo and Lau described the Ccn1-null mouse showing severe septal defects with complete penetrance [8]. Therefore, CCN1 was considered a promising candidate gene for ASD in man.…”

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

“…In addition, it is established that senescence and SASP affect tissue and organ function in a context‐dependent manner 12, 28. For example, CCN1 is essential to the proliferation of certain cell types 29, 30. By contrast, CCN1 can induce cell apoptosis and senescence during cancer development and fibrosis.…”

Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure

“…Both of them modulate cellular responses through interaction with integrins and regulate adhesion, migration, proliferation, differentiation, survival of cells and apoptosis [1]. CCN proteins are necessary in the process of cardiac development and their expression in the ventricular myocardium is upregulated after myocardial infarction or in chronic heart failure [2,3]. Basal CCN2 expression in the atria of adult mice has been described as being higher than its physiological ventricular level, while the expression of CCN1 in the atria has not been examined to date.…”