Faithful tissue-specific expression of the human chromosome 21-linked COL6A1 gene in BAC-transgenic mice

Abstract

We created transgenic mice with a bacterial artificial chromosome (BAC) containing the human COL6A1 gene. In high-copy and low-copy transgenic lines, we found correct temporal and spatial expression of COL6A1 mRNA, paralleling the expression of the murine Col6a1 gene in a panel of nine adult and four fetal organs. The only exception was the fetal lung, in which the transgene was expressed poorly com- pared with the endogenous gene. Expression of COL6A1 mRNA from the transgene was copy number-dependent, and the increased gene dosage correlated with increased production of collagen VI alpha 1 in skin and heart, as indicated by Western blotting and immunohistochemistry. COL6A1 maps to Chromosome 21 and this gene has been a candi- date for contributing to cardiac defects and skin abnormalities in Down syndrome. The low-copy and high-copy COL6A1 transgenics were born and sur- vived in normal Mendelian proportions, without cardiac malformations or altered skin histology. These data indicate that the major promoter and enhancer sequences regulating COL6A1 expression are present in this 167-kb BAC clone. The lack of a strong cardiac or skin phenotype in the COL6A1 BAC-transgenic mice suggests that the increased expression of this gene does not, by itself, account for these phenotypes in Down syndrome