Transchromosomic cell model of Down syndrome shows aberrant migration, adhesion and proteome response to extracellular matrix

Here we show that aberrant adhesion and proliferation of DS cells can be reproduced using a transchromosomic model of DS (mouse fibroblasts bearing supernumerary HSA21). We also demonstrate a deacrease of cell migration in transchromosomic cells independently of their adhesion properties. We show that cell-autonomous proteome response to the presence of Collagen VI in extracellular matrix is strongly affected by trisomy 21.This set of experiments establishes a new model system for genetic dissection of the specific HSA21 gene-overdose contributions to aberrant cell migration, adhesion, proliferation and specific proteome response to collagen VI, cellular phenotypes linked to the pathogenesis of CHD.Down syndrome (DS), a congenital condition caused by the trisomy of human chromosome 21 (HSA21), is the most frequent chromosomal abnormality in live births associated with mental retardation and congenital heart defect (CHD) [1]. Although the pathology of DS is associated with a number of complex manifestations [1-3], the presence of a congenital heart defect (CHD) is the greatest risk factor for death during infancy. Approximately 40% of liveborn DS infants are born with a CHD [4], the majority of which involve abnormal development of the atrioventricular canal (AVC). Although CHD occur as isolated abnormalities in otherwise normal children, >50% of AVC defects are diagnosed in DS infants [5]. The association between DS and AVC defects has led to speculation that proteins encoded on chromosome 21 are involved in cardiac valve development. Molecular mechanisms responsible for the development of AVC defects are not known, and their protein cause has not yet been firmly assigned to trisomic contributions of specific HSA21 genes. A currently accepted stochastic model [6] predicts that increased cell adhesion causes the decreased migration of trisomy 21 cells preventing normal AVC formation. The crucial underlying process is the cellular response to changes in extracellular