Increased adhesiveness of Down syndrome fetal fibroblasts in vitro.

Abstract

We compared the in vitro rate of divalent cation-independent aggregation of fibroblasts derived from abortuses with normal karyotypes and with trisomy 21 (Down syndrome). Fibroblasts from five lung and two of three cardiac cultures from subjects with Down syndrome aggregated more rapidly than matched fibroblasts from normal controls or lung fibroblasts from an abortus with trisomy 13. In contrast, skin fibroblasts derived from the trisomy 21 subjects had low rates of aggregation. The high rates of aggregation of trisomy 21 lung fibroblasts were not affected by hyaluronidase treatment. Lung fibroblasts from both normal and Down syndrome subjects had similar membrane polarization values in an assay using the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene. Thus, the increased aggregation rate we observed for trisomy 21 fibroblasts was restricted to specific fibroblast cultures, was not mediated by hyaluronic acid or gross membrane lipid alterations, and was specific for trisomy of chromosome 21. As illustrated in computer simulations presented elsewhere, increased intercellular adhesiveness during organogenesis could explain the frequent occurrence of malformations, including pulmonary hypoplasia and congenital heart defects, in Down syndrome.

Endocardial cushion defect: Further studies of “isolated” versus “syndromic” occurrence

“…This congenital heart defect is characteristically associated with trisomy 21 in humans and with its animal equivalent (mouse trisomy 16) [Miyabara et al, 19821, suggesting that specific genetic factors are involved in the morphogenesis of ECD [Wright et al, 1984;Boughman et al, 19881. Analysis of clinical data suggested that ECD of the Certain associated CVMs are equally frequent in either Down or Ivemark syndrome, regardless of the presence of ECD. These associations may be influenced by yet undefined determinants of the syndrome itself.…”

Mechanisms in the Pathogenesis of Congenital Cardiac Malformations

“…Against this idea, cellular adhesion is increased in fibroblasts obtained from Down syndrome patients. [60] Children with Down syndrome have a distinctive spectrum of heart malformations. They frequently have endocardial cushion defects but rarely have conotruncal or aortic arch abnormalities.…”

Down syndrome congenital heart disease: A narrowed region and a candidate gene

“…Dramatic decreases in the expression of another Ig-CAM, NCAM, occur in cells of the endocardium during epithelial-mesenchymal transformation. 55,56 We speculate that the overexpression of DSCAM may have the potential to perturb epithelial-mesenchymal transformation and/or the migration and proliferation of mesenchyme cells, and possibly thus contribute to the increased intercellular adhesion seen in DS cushion fibroblasts 8 and the abnormal cushion development seen in DS-CHD. Further questions include whether DSCAM effects are mediated through homophilic adhesion, as suggested by recent studies in mouse fibroblasts 54 or through heterophilic adhesion and signaling interactions involving coreceptors and other cushion molecules.…”

“…html). Further, both the etiology of characteristic DS heart defects and the increased intercellular adhesiveness of DS cardiac fibroblasts 8 implicate disturbances in cell adhesion as underlying DS-CHD. Of the 64 known and predicted genes 20 identified in the narrowed DS-CHD candidate region to date, DSCAM is the only one which has been shown to mediate cell-cell adhesion.…”

“…7 Based both on the aberrant cell adhesion observed for DS cardiac fibroblasts and on subsequent computer modeling that supported the assertion, DS-CHD was proposed to be due to increased expression of molecules involved in cell adhesion. 8,9 This hypothesis suggests the existence of a gene or gene cluster on chromosome 21, which is involved in cell adhesion and likely plays an important role in valvuloseptal morphogenesis, but when overexpressed, results in the defects of DS-CHD.…”