Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development

Abstract

To expand our insight into cardiac development, a comparative DNA microarray analysis was performed using tissues from the atrioventricular junction (AVJ) and ventricular chambers of mouse hearts at embryonic day (ED) 10.5-11.0. This comparison revealed differential expression of approximately 200 genes, including cartilage link protein 1 (Crtl1). Crtl1 stabilizes the interaction between hyaluronan (HA) and versican, two extracellular matrix components essential for cardiac development. Immunohistochemical studies showed that, initially, Crtl1, versican, and HA are co-expressed in the endocardial lining of the heart, and in the endocardially derived mesenchyme of the AVJ and outflow tract (OFT). At later stages, this co-expression becomes restricted to discrete populations of endocardially derived mesenchyme. Histological analysis of the Crtl1-deficient mouse revealed a spectrum of cardiac malformations, including AV septal and myocardial defects, while expression studies showed a significant reduction in versican levels. Subsequent analysis of the hdf mouse, which carries an insertional mutation in the versican gene (CSPG2), demonstrated that haploinsufficient versican mice display septal defects resembling those seen in Crtl1(-/-) embryos, suggesting that reduced versican expression may contribute to a subset of the cardiac abnormalities observed in the Crtl1(-/-) mouse. Combined, these findings establish an important role for Crtl1 in heart development.

Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart

“…For example, individuals with Down syndrome (Trisomy 21) have remarkably similar types of AVSD that are associated with defects in DMP expansion (Blom et al, 2003). AVSD is also observed in the Ts16 Down syndrome mouse model, in which the DMP is deficient (Webb et al, 1999;Snarr et al, 2007). Here, we demonstrate that AVSD can be the direct result of defective DMP development in mice.…”

“…However, new findings suggest that AVSDs seen in perinatal humans are more complex in their origins. Previous work has demonstrated that deficient DMP development occurs in mouse (Webb et al, 1999;Snarr et al, 2007b;Wirrig et al, 2007) and human (Blom et al, 2003) fetuses with AVSD. As such individuals exhibit malformations in other septal structures, the specific role of DMP defects in generating these malformations has been unclear.…”

Isl1 Expression at the Venous Pole Identifies a Novel Role for the Second Heart Field in Cardiac Development

“…11 Thus, as we continued to gain more insight into the matter we opted to use this terminology. 7,12 We acknowledge, however, that "atrial spine", "vestibular spine", and "spina vestibuli" are also commonly, and legitimately, used in other articles to describe this mesenchymal population.…”

Molecular Cloning and Developmental Expression of a Hyaluronan and Proteoglycan Link Protein Gene,crtl1/hapln1, in Zebrafish

“…In addition to tissue colocalization, studies using recombinant proteins have demonstrated the molecular interactions of Crtl1/ Hapln1 in the formation of other proteoglycan aggregates, versican and neurocan (Matsumoto et al, 2003;Shi et al, 2004;Rauch et al, 2004). Although expression of Crtl1/ Hapln1 was reported in several developing tissues (Binette et al, 1994;Deak et al, 1999;Wirrig et al, 2007, Shibata et al, 2003, Colas and Schoenwolf, 2003, a detailed embryonic expression analysis is required for understanding its biological roles. Furthermore, cross-species comparison of Crtl1/Halpn1 would shed light on the evolutionary conservation and/or diversity of the structure and function, though such study has not yet been performed.…”