International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


VERNE CHAPMAN MEMORIAL LECTURE

MONDAY OCTOBER 18

7.30pm – 8.30pm

25 YEARS OF TRANSGENIC MICE: THE METALLOTHIONEIN PERSPECTIVE

Palmiter RD

Howard Hughes Medical Institute and University of Washington, Seattle, United States

Our venture into mouse genetics started with the cloning of the mouse metallothionein I (Mt1) gene in 1979.  We showed that metals, glucocorticoids, and cytokines induced transcription of the Mt1 gene.  The Mt locus is amplified in cells resistant to cadmium toxicity, but inactivated by DNA methylation in other cell lines.  In pursuit of understanding the transcriptional regulation by metals, we fused the 5’ flanking region of Mt1 gene to the coding region of HSV-thymidine kinase to produce MT-TK and sent it to Ralph Brinster for injection into mouse eggs.  These experiments along with mutational analysis were used to identify the metal response elements that allow induction by metals.  More importantly, they launched a 15-year collaboration with Ralph Brinster making and studying genetically modified mice.  The MT-TK transgenic mice were the first that demonstrated expression, regulation, methylation and germline transmission of a functional transgene.  Input from Vern Chapman and colleagues at Roswell Park in 1981 contributed to the “big mouse” experiments that demonstrated how transgenic technology could alter the phenotype of mice.  While endeavouring to understand how enhancers work, we discover that SV40 T-antigen is a potent oncogene.  Meanwhile, the odd transmission of MT-TK transgene in one line of mice, in which males were fertile but never transmitted the transgene, let to the discovery of HSV-TK toxicity and transgene deletion by homologous recombination.  Later, while studying knockout mice lacking Mt1 & Mt2, we learned that these genes are not essential but do protect against cadmium toxicity and oxidative damage.  Vern Chapman’s research allowed us to understand the female lethality of mice lacking Mt1&2 and the Menkes copper transporter, Atp7a.  We maintain an interest in Mt gene regulation and function, but the lab currently uses an array of contemporary genetic techniques to explore the neurobiology of motivation, appetite, and learning.  But, we would not have gotten there without our foray into Mt genetics. 

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