Like a handful of sand thrown in the air, scatter factor (SF) causescells to scatter across the surface of a culture dish. As is true for mostgrowth factors, this one was named for its first found effect oncultured cells. However, further study of growth factors almostalways leads to the identification of additional functions. This, inturn, often results in the coining of different names for the samegrowth factor. In the case of SF, because of its essential function innormal liver development, SF's more informative alternative name ishepatocyte growth factor (HGF).
As a growth factor gene is identified and researchers catalogue moreand more effects, the true extent of its biological role becomesclearer. SF/HGF has reached this stage.
In two articles published in Thursday's issue of Nature, scientistsreport that this growth factor also plays a key role in placentaformation and maintenance, and thus in normal mammalian gestation.Both groups of scientists study the embryonic development oftransgenic mice in which the SF/HGF gene is "knocked out."
In the article entitled, "Scatter factor/hepatocyte growth factor isessential for liver development," Carmen Birchmeier and hiscolleagues at the Max-Delbruck Laboratory, in Koln, Germany, showthat these transgenic mice die before birth, having very poordevelopment of the liver and placenta. In the article entitled,"Placental defect and embryonic lethality in mice lacking hepatocytegrowth factor/scatter factor," Naomi Kitamura and her colleagues atthe Kansai Medical University, in Osaka, Japan, focus onunderstanding the deterioration of the placenta that is seen duringpregnancy in these transgenic mice.
Sometimes Knockout Mice Just Die
Transgenic mice with one of its paired SF/HGF genes knocked outwere bred to produce homozygous offspring with non-functionalSF/HGF genes on both pairs of the chromosome containing this gene.When this was done, neither research group saw any live births ofhomozygous offspring. This implied that the mutant homozygousembryos died during pregnancy.
In fact, as pregnancy progressed, the scientists observed increasingnumbers of dead fetuses. These turned out to be the homozygousones with two non-functional SF/HGF genes. Between days 14 and16 of pregnancy, the percentage of live fetuses with both pairs ofSF/HGF genes knocked out declined from the expected 25 percent to2 percent.
As expected for mutant embryos lacking SF/HGF genes,Birchmeier's group observed livers that were severely reduced in sizeand number of cells. Liver cells were undergoing a distinctiveprogrammed cell death process known as apoptosis. However, theblood cell-forming cells in the liver appeared normal.
SF/HGF's Role Expanded, Clarified
Both research groups observed abnormalities in the placentas of micepregnant with these mutants. Kitamura and colleagues found that theplacental labyrinth, the region where small fetal blood vessels arebathed in maternal blood, was disorganized and poorly developed.This defect appears just at the time when the placenta begins tofunction as the primary nutrient transport system for the fetus.Kitamura hypothesizes that this is the cause of fetal death.
SF/HGF is believed to be important for a number of other biologicalprocesses that occur during development. Chief among these areearly development of the nervous system, formation of tubularinternal organs, and induction of blood vessels. In light of this,Birchmeier and Kitamura were surprised to find normalcardiovascular and central nervous systems and internal organs in themutant mice.
So, even though these mutants die as fetuses, the understanding ofSF/HGF's biological role has been advanced. A previouslyunrecognized effect of SF/HGF on placenta formation has beenadded while its other effects on development now seem lessimportant. According to Birchmeier, the next step should be a moresubtle one. He advocates the use of conditional SF/HGF geneinactivation in specifically chosen tissues as a way of furthercharacterizing the most important biological functions of this growthfactor. n
-- Chester Bisbee Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.