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Glue-like protein offers new key to understanding birth defects

Scientists at the Whitehead Institute for Biomedical Research have discovered a glue-like protein in fruit flies that ensures proper partitioning of hereditary material and could shed new light on the origin of some of the most common human birth defects, including Down syndrome.

MIT Associate Professor Terry Orr-Weaver and her colleagues described the new protein, called MEI-S332, and its role in sexual reproduction in the October 20 issue of Cell.

MEI-S332 is the first protein in any species shown to hold together chromosomes until the exact moment in cell division when they must separate to ensure proper development of eggs and sperm.

In humans, the partitioning of chromosomes-the threadlike structures that transmit our genetic inheritance-is one of the most delicate steps preceding the birth of a healthy child. Before conception, a single reproductive cell divides twice to produce four separate eggs or sperm cells. During these cell divisions, the chromosomes group and regroup in an elaborate dance to ensure that each daughter cell receives the precise number and types of chromosomes required for normal life. But more often than might be expected, the mechanisms regulating chromosome separation fail.

Scientists estimate that the partitioning process goes awry in about 10 percent of human conceptions, leaving some embryos with too many chromosomes and others with too few. In fact, these errors in chromosome segregation account for more than half of all early miscarriages. Embryos that do survive to term exhibit a range of birth defects, from Down syndrome, which occurs in one in 700 live births, to trisomy 13, a much rarer disorder causing death before three months of age.

Dr. Orr-Weaver and her colleagues at the Whitehead Institute are exploring how and why these problems arise. Their work focuses on the fruit fly Drosophila melanogaster because researchers historically have accumulated a great storehouse of genetic information about Drosophila and because the flies are easy to manipulate in the laboratory. Modern science has shown that vital gene processes are often conserved across species; thus, studies of development in fruit flies can provide important clues about the molecular mechanisms underlying human birth defects.

MEI-S332, discovered by Dr. Orr-Weaver and her colleagues, Dr. Anne W. Kerrebrock, Daniel P. Moore and Jim S. Wu, plays a critical role in keeping the chromosome segregation process on track in both eggs and sperm. It binds together chromosome copies during meiosis, the basic program for sexual reproduction. Scientists have been searching for such a protein for years.

"The isolation of MEI-S332 should help us identify analogous proteins in other species, including human beings," Dr. Orr-Weaver said. "In addition, we can begin hunting for proteins that interact with MEI-S332; these, in turn, will lead us to additional proteins and eventually allow us to decipher the entire system of molecules that participate in chromosome segregation."

Ultimately, MEI-S332 could provide the key to understanding the origins of some of the most common birth defects.

Understanding meiosis

Meiosis begins in the reproductive cells that give rise to eggs and sperm. These cells, like all other cells in the body, carry two separate copies of each human chromosome, for a total of 46 chromosomes (or 23 homologous pairs). The goal of meiosis is to generate eggs and sperm that carry only one copy of each type of chromosome so that when an egg and sperm unite, the resulting embryo again has a full set of 46-no more and no less.

Surprisingly, the first act of meiosis begins with duplication of the chromosomes rather than separation. The duplicates, known as "sister chromatids," remain firmly attached to each other. Acting as a single unit, they line up in the cell opposite the two sister chromatids that make up their homologous counterpart. When the line-up is complete, the cell division apparatus-a framework resembling a system of guide wires anchored at each end of the cell-pulls the homologous chromosomes apart. The reproductive cell divides, resulting in two cells each containing 23 sister chromatid units (but still 46 chromosomes in total).

The final division of chromosomes occurs in the second act of meiosis, when the sister chromatids again line up in the middle of the cell and the cell division apparatus reforms. The guide wires gently pull apart the sister chromatids and the cell divides again, producing a gamete (an egg or a sperm) with 23 individual chromosomes.

The Role of MEI-S332

MEI-S332 is the glue that holds sister chromatids together between the first act of meiosis and the second. When it is absent, as in fruit flies that carry a mutation in the mei-S332 gene, the sister chromatids fall apart early. This is most evident at the beginning of the second act of meiosis, when the sister chromatid units should be lined up in an orderly row, waiting for the guide wires to pull them apart. In reproductive cells from mei-S332 mutant males, the contents are anything but orderly. The sister chromatid units are gone, replaced by a jumble of individual chromosomes. When the cell attempts to divide, some chromosome copies are caught on the wrong side of the dividing line-thus, some gametes receive too many chromosomes and others too few.

"Initially, we did not know whether the mei-S332 gene produced the glue itself or a regulatory protein that directed other genes to hold the sister chromatids together," Dr. Kerrebrock said.

To answer this question, the researchers used genetic engineering to create a hybrid protein consisting of MEI-S332 and a fluorescent protein from jellyfish. Photographs of meiotic cells containing this brilliant green protein clearly show that MEI-S332 sits at the center of each sister chromatid pair until the precise moment when the sister chromatids must separate to enter their new cells.

Mr. Moore said, "This localization study was very important, because it demonstrated that MEI-S332 participates directly in sister-chromatid cohesion; it is the glue that holds the sister chromatids together. Moreover, it appears that separation of the sister chromatids cannot occur until MEI-S332 is destroyed or released from the sister-chromatid unit."

"Determining how MEI-S332 associates with the chromosomes and how it disappears will provide critical insights into proper chromosome segregation and the regulation of key transitions in meiosis," Dr. Orr-Weaver concluded.

This work was funded by a grant from the National Science Foundation and a postdoctoral fellowship from the Medical Foundation to Dr. Kerrebrock.

A version of this article appeared in MIT Tech Talk on October 25, 1995.

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