BioWorld International Correspondent

LONDON - Insights into the causes of low birth weight in humans are likely to follow the discovery of a murine gene that controls the growth of the placenta and the flow of nutrients from mother to fetus.

The gene in question, which encodes insulin-like growth factor II (IGFII), was already known to be important for fetal growth, and is involved in the pathogenesis of Beckwith-Wiedemann syndrome, a rare overgrowth condition characterized by high birth weight and rapid weight gain after birth. In addition, IGFII is deregulated in several human cancers.

As well as physiologists, both geneticists and evolutionary biologists will be interested in the finding as it contributes to the debate about why some genes are expressed by only one of the alleles inherited from the father and the mother, and not by both.

Miguel Constancia, a postdoctoral researcher in a team led by Wolf Reik at the Babraham Institute in Cambridge, told BioWorld International: "It is too early to extrapolate our work from mice to humans. It will, however, be very interesting to see whether this gene, which is expressed in the murine placenta, behaves in the same way in humans. If it does, then it may be possible to ascribe some cases of growth retardation in humans to its lack in the placenta."

Constancia, along with his colleagues in Cambridge and collaborators in Manchester, Canada and Germany, reports the findings in Nature in a paper titled "Placental-specific IGF-II is a major modulator of placental and fetal growth."

Commenting on the paper in a "News & Views" article in the same issue of Nature, titled "Piece of cake," Benjamin Tycko and Argiris Efstratiadis, both of Columbia University College of Physicians and Surgeons in New York, write that the discovery has some "truly exciting implications for fetal physiology."

Reik and his team knew that IGFII is expressed both in fetal tissues and in the placenta, and set out to discover what the function of the gene's product was in the placenta alone. Constancia said: "We had identified one RNA transcript of IGFII out of many, which was only present in the placenta. It was responsible for about 10 percent of IGFII transcripts in the placenta - although we have no idea what proportion of IGFII protein it accounts for."

They went on to produce a mutant mouse in which that particular IGFII transcript was knocked out, while leaving fetal expression of IGFII at a normal level. During gestation, the researchers found that the placentae of the mutants were significantly smaller than normal. Further experiments demonstrated that the flow of nutrients from mother to fetus also was reduced.

"Interestingly, we found that the fetuses were of normal size in mid-gestation, even though the placentae were small," Constancia said. "But by the end of gestation, the growth of both fetuses and placentae was retarded. This was puzzling. Later experiments showed that these small placentae attempted to compensate by actively transporting nutrients to the fetuses early in pregnancy - working harder than normal to meet the demands of the fetuses." As gestation continued, however, the placentae could not keep up with the fetuses' needs, and fetal growth also began to fail.

The group now is planning to study the IGFII gene in humans, examining its expression in full-term placentae, particularly those that are relatively small and associated with low-birth-weight babies. Future studies in mice will investigate the exact nature of the fault in nutrient transport in the existing mutant mice, with the aim of determining how the supply of nutrients across the placenta from mother to fetus is controlled.

For geneticists, Constancia said, the interest in the finding concerns its support for a theory explaining why some genes are transcribed only by the allele inherited from the father, or only by that inherited by the mother. By contrast, most genes are transcribed by both the paternally inherited allele and the maternally inherited allele. That phenomenon is called genetic imprinting.

The best-known theory to explain why genetic imprinting occurs is called the conflict theory. This holds that there is a conflict between the interests of the parental genomes in terms of extracting maternal resources to support the offspring, with the paternal genome standing to benefit from promoting the growth of the offspring, while the maternal genome may benefit from limiting the growth of the offspring. According to this theory, paternally expressed imprinted genes will be growth promoting, and maternally expressed imprinted genes will be growth suppressing.

"These predictions seem to hold for a number of imprinted genes that have been identified so far," Constancia said. "The transcript of the murine IGFII gene that is present only in the placenta, and which we studied, is paternally expressed and so this finding supports the conflict theory."