When One Gene Has Two Roles, Its Second Function May Be Missed

r two copies of the gene for GATA-2. When two such mice are bred, one-fourth of the resulting embryos will lack both copies of the GATA-2 gene.

"These gene-knockout mice die early in embryogenesis," Engel said. The GATA-2 defect is unknown in humans, he said, presumably because it results in very early miscarriage. Mice and humans are very similar in the genetic mechanisms of their embryonic development.

In an effort to understand the signals that cause GATA-2 to turn on in the embryonic tissues that eventually produce blood cells, the researchers constructed a huge piece of DNA called an artificial chromosome. This artificial chromosome contains the GATA-2 gene plus long stretches of the DNA that brackets it in the normal chromosome. When the artificial chromosome was injected into mouse embryos that lacked GATA-2, blood cell formation was restored, or "rescued," and live mice were born.

Surprisingly, however, despite a normal blood forming system, all the mice died shortly after birth. Post-mortem examination revealed that they had malformations of the kidneys and bladder and other genitourinary structures.

"When we went back and looked at normal mice, we found that GATA-2 is expressed in a lot of the organs in the developing urogenital system," Engel said. GATA-2 had been thought to be important only for blood cell formation.

"And what was really surprising," he continued, "was that in the knockout mutants, the artificial chromosome, with GATA-2 and that enormous length of flanking DNA, was not sufficient to rescue the urogenital system."

The researchers conclude that GATA-2 expression in developing genitourinary tissues must be governed by a regulatory DNA sequence a vast distance away from the GATA-2 gene itself.

"The latter surprise is going to be disturbing to the scientific community, because everybody thinks that you control genes with relatively small pieces of DNA located right next to the gene," Engel said. "As far as I know,

Contact: Bill Burton
Northwestern University

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