Of mice and men: sharing locator genes.

Of mice and men: Sharing locator genes

beginning life as a microscopic, amorphous blob, an embryo undergoes numerous divisions to form clusters of specialized cells. Some eventually become nerves; others develop into skin, muscles or blood. But even before these cells take on their destined shapes and functions, certain genes in the developing embryo lay out a master blueprint, specifying from head to tail where major sections of the body will lie. Now, researchers have discovered compelling new evidence that creatures as diverse as fruit flies and mice share a common set of genes for organizing the body's architecture.

While the new study focuses on manipulating embryonic development in the mouse, investigators say the striking similarity between this animal's genetic makeup and that of humans indicates the work may also provide a better understanding of human fetal development. Osamu Chisaka and Mario R. Capecchi of the University of Utah School of Medicine in Salt Lake City report their findings in the April 11 NATURE.

"It's the most beautiful and amazing and fantastic thing--that there is a common, unifying link between flies and humans," declares development biologist Brigid Hogan of Vanderbilt University Medical School in Nashville. "You can use the genetics of flies and the relevance of the mouse model to humans to start to ask very, very detailed questions about human embryonic development," she adds.

The gene that the Utah researchers studied belongs to a group called homeobox genes, which scientists discovered a decade ago in fruit flies. Each gene, depending on its location, helps determine which groups of cells will develop as a particular body segment, and where their structure may reside. Looking at fruit flies, investigators had found that genes lying closer to the head determined development of features there; those nearer the tail orchestrated posterior development. In the early 1980s. genetics reportd that disrupting one of the front-end fruit fly genes caused a body alteration worthy of a sci-fi movie: Instead of antennae, legs grew from the fly's head. Other researchers later discovered homeobox genes with identical DNA sequences in mice, humans and other vertebrates. But whether these shared genes also orchestrate development remained largely unknown.

In their new experiment, Capecchi and Chisaka used a method called gene targeting to insert into mice embryos two copies of a mutant homeobox gene, called Hox-1.5. Mice born with the resulting mutation had no thymus, an organ critical for regulating the immune systm. The mice, which all died within 12 hours, also had abnormal parathyroid function and detective hearts and arteries -- characteristics of a life-threatening human birth defect called DiGeorge syndrome.

Although the defective gene in mice appears on a different chromosomes than the one implicated in about 20 percent of people with DiGeorge syndrome, Hox-1.5 might still play a role in the human disorder, Capecchi told SCIENCE NEWS. He speculates that several genes working in concert, including Hox-1.5, may cause the syndrome, or that the gene may trigger the disorder by activating a gene above or below it.

"Any lingering doubts that homeobox genes are important regulators of vetebrate [development] should be dispelled" by Cappechi's study, write Hogan and her Utah colleague Christopher Wright in a commentary accompanying the NATURE paper.

Cappechi plans to disrupt several other of the 40 or so homeobox genes in mice in hopes of elucidating their function. "We want to get a feeling for what the whole complex of 40 are doing...which genes are talking to each other," he says. He also seeks to determine whether embryonic cells destined to form part of the nervous system, which interact with homeobox genes, directly cause defects -- or it these cells must migrate elsewhere in the embryo to do damage.