COMPLEMENTATION OF NULL CF MICE WITH A HUMAN CFTR YAC TRANSGENE

We have made transgenic mice carrying a 320 kb YAC with the intact hum an cystic fibrosis transmembrane regulator (CFTR) gene, Mice that only express the human transgene were obtained by breeding with Cambridge null CF mice, One line has approximately two copies of the intact YAC, Mice carrying this transgene and expressing no mouse cftr appear norm al and breed well, in marked contrast to the null mice, where 50% die by similar to 5 days after birth, The chloride secretory responses in these mice are as large or larger than in wild-type tissues, Expressio n of the transgene is highly cell type specific and matches that of th e endogenous mouse gene in the crypt epithelia throughout the gut and in salivary gland tissue, However, there is no transgene expression in some tissues, such as the Brunner's glands, where it would be expecte d, Where there are differences between the mouse and human pattern of expression, the transgene follows the mouse pattern, We have thus defi ned a cloned fragment of DNA which directs physiological levels of exp ression in many of the specific cells where CFTR is normally expressed .