Renewing and regulating cells in the bloodstream is one of the mostcomplex tasks that the body performs. The correct ratios of red andwhite blood cells as well as the appropriate numbers of the largevariety of types of these cells must be accurately maintained at alltimes. If this is not done, diseases such as anemia and cancer canoccur. In addition, unlike the majority of other cells in the body,blood cells must be maintained in the face of a rapid rate of turnoverand clearance.

Scientists now have a good understanding of the processes thatcontrol cell growth. However, removal of cells is also critical formaintaining the status quo in fast growing cellular systems such asthe blood. In recent years, scientists have begun to unravel the detailsof the process by which cells are naturally removed from the body.This process is called programmed cell death or apoptosis.

In the March 10 Science, several articles describe the current state ofknowledge concerning apoptosis. In one of these articles, entitled,"Massive cell death of immature hematopoietic cells and neurons inbcl-x-deficient mice," the role of the bcl-2 gene family in themaintenance of developing blood cells and neurons is described.Noboru Motoyama and his colleagues from the Howard HughesMedical Institute at Washington University School of Medicine in St.Louis show that deletion of the bcl-x gene has profound effects on thedevelopmental program of blood cells and neurons.

Immature Cells Saved From Committing Suicide

Transgenic mice in which the bcl-x gene was knocked out died beforebirth at around embryonic day 13. Extensive cell death by apoptosiswas seen primarily in blood-forming cells and neurons. Blood-forming or hematopoietic cells in the developing liver were onetarget. Immature neurons in the developing brain that had undergonecell division were the second target.

In order to overcome the problem of embryonic cell death, theinvestigators constructed chimeric mice in which some cell lineagescontained the knocked out bcl-x gene and others did not. Analysis ofthese mice showed that the maturation of lymphocytes with the bcl-xgene knocked out was diminished. The life-span of immaturelymphocytes was shortened if they were missing the bcl-x gene.

Thus, the bcl-x gene supports the continued existence of immaturecells during the development of the nervous and hematopoieticsystems. It was previously known that bcl-x and other members of thebcl-2 gene family inhibited apoptosis. However, this study shows thatbcl-2 exerts its effects on immature, developing cells.

In previous work, early embryonic death was expected for mice inwhich the bcl-2 gene was knocked out because of this gene beingwidely expressed in developing embryos. But these bcl-2-deficientmice did not die before birth. In fact, they showed little in the way ofabnormalities, leading researchers to conclude that this geneprevented apoptosis in mature cells and that other members of thegene family could take over the function of bcl-2.

With this as background, researchers suspected that bcl-x would workin a similar way. But, as Kevin Roth, pathologist and co-author of thepaper, said, "The extent of cell death was impressive. We weresurprised to see how extensive the cell death was and how criticalbcl-x is to survival of the mouse embryos."

In these mice, Roth stated that, "If you don't have bcl-x, there isn'tanything else to replace it. It could be that bcl-x keeps the immaturecells alive, enabling them to mature. Then, bcl-2 is turned on to keepthe mature cells alive."

These researchers were able to determine that programmed cell deathoccurred independently in the embryonic blood and nervous systemsof mice without bcl-x. The loss of blood isn't causing neuronaldeath," explained Roth. "It appears that bcl-x is crucial to thedevelopment of both the blood system and the nervous system."

The findings by Dennis Loh's group will enable researchers to focustheir attention on the role of programmed cell death in earlyembryonic development of the blood and nervous systems. Immunecells are routinely eliminated if they are recognized as a danger to thebody's own cells. And as an embryo's brain develops, scores ofunnecessary neurons naturally undergo cell death.

These scientists hope that further research will point to why somecells are selected to live while others are programmed to die. As theytold BioWorld Today, these investigators now plan to generate micein which both the bcl-x and bcl-2 genes are manipulated in order todetermine the roles of this gene family in cell survival duringdevelopment. n

-- Chester Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.