When Adam and Eve conceived Cain and Abel, the union of theirsperm and ova created more than just embryos. It incited aconstellation of genes to encode the constituents of various extra-embryonic membranes, eventuating in production of the placenta.Until this temporary organ is fully formed, the fertilized mammalianegg lives off the nutrients provided by direct maternal secretion. By thetime this burgeoning blob of dividing stem cells has implanted itself inthe wall of the uterus _ in mice, after about five days _ the placentais ready to take over and supply the growing embryo with food, oxygenand waste-disposal services.In ancient Greek, the word "placenta" meant "little cake." In fact, inshape, a human placenta does resemble a thick (one and one-half inch)round (seven-inch diameter) pancake. In edibility, placentas, which arerich in growth factors, are routinely eaten by many mammals,including primitive human tribes. And some devotees of the currentNew Age enhance their awareness of self and nature by ingesting theplacentas of their newborns.A Gene Named MashMash-2 is the name of a mouse gene that encodes a transcription factorleading to the generation of a placenta. It gets its name, MammalianAchaete-scute Homologue, from similar sequences in the genome ofthe fruit fly (Drosophila melanogaster). In that insect, Mash-2 controlsdevelopment of the nervous system.Mammalian Mash-2 is still pretty much of a mystery, saiddevelopmental biologist Franois Guillemot. He is the first author of apaper in this week's Nature (Sept. 22), titled "Essential role of Mash-2in extra-embryonic development."It reports that transgenic mice, lacking the Mash-2 gene, die halfwaythrough their 21-day gestation for lack of a placenta. That auxiliaryorgan is programmed to kick in at 10.5 days after coition kicks off themurine reproductive process. In human gestation, the cut-off is at 15 or16 days.Guillemot, a post-doc now at the French National Center for ScientificResearch in Strasbourg, did his placental experiments in Toronto, asmember of a group at Mt. Sinai Hospital. "Guillemot cloned the Mash-2 gene, and knocked it out of embryonic mouse stem cells byhomologous recombination," developmental biologist Andras Nagytold BioWorld Today.Rescuing The Afterbirth-Lacking EmbryosNagy then rescued the resulting mutant female mice from dying, forlack of a placenta, by inserting intact cells in the pre-implantationembryos to restore placental development. His trick was to render theMash-2-minus embryos chimeric, so that only certain of their cellsaccepted the fix."The beauty of the whole story," Nagy observed, "is that this is a mid-gestation lethal phenotype," which by definition is slated for still-birth.To other researchers "working with knockouts of any genes," heconveys this message: "In knocking out embryonic stem cells, it is veryimportant, when characterizing the embryo, to make sure that there isnothing wrong with the placenta."He continues: "If we are not aware of the placenta, we might thinkthere is something wrong with an embryo that grows normally until itdies at 10.5 days. Mash-2 is a very nice example that there is nothingwrong with the embryo; that the defect is extra-embryonic."Nagy now heads his own laboratory at Mt. Sinai's Samuel LunenfeldResearch Institute."We observed that the gene is absolutely required for placentaldevelopment, and thus for survival of the embryo physically,"Guillemot told BioWorld Today. In France, he continues to work onMash-2's role in developing extra-embryonic tissues, as well as on thatgene's look-alike, Mash-1, which controls nervous-system developmentin mice.The Mash-2 gene maps to chromosome 7 on the mouse genome. Thiscorresponds to chromosome 11 in humans. "There is an aberrationdeletion or inversion of chromosome 11," Nagy said, "where theremight be a chance that Mash-2 is involved in human disease, possiblyby the breakpoint of the chromosome inversion."He and his Toronto co-workers are now beginning to pursue the humangene, in collaboration with molecular biologist Jeremy Squire atToronto's Hospital for Sick Children."Chromosome 11 is a very interesting area in humans," Squire toldBioWorld Today. "We are interested in defects of imprinting , and wesuspect that Mash-2, so far unknown in the human genome, may besomehow involved in that particular region, which is highly imprinted.It immediately becomes a candidate for study of the human condition."Squire added, "We only suspect that the gene resides on chromosome11, because that part of the mammalian genome is highly conservedbetween mice and humans. Within the next few weeks, we shouldknow exactly where it is." He is probing the region by fluorescent insitu hybridization.Nagy explained: "We expect that the Mash-2 gene in mice will prove tobe imprinted. This means that the paternal allele [parental gene variant]has switched off after implantation. Only the maternal allele isexpressed."Squire's interest in the origin of the placenta is as much clinical asacademic.He is looking at a growth disorder, Beckwith-Weideman syndrome, inwhich "children are quite large at birth, and have a bulky appearance.By the time they reach adult life they're back to normal."But, he added, "kids with the syndrome have a high incidence ofseveral solid tumors. So it seems as if the constitutional change in theinsulin-like growth-factor gene [also on that chromosome 11imprinting hot spot] and possibly Mash-2 may predispose tomalignancy."Squire observed that "the placenta itself is a bit like a tumor in the wayit invades the body. Perhaps from it we may gain some insights intosporadic cancer." n

-- David N. Leff Science Editor

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