A Brisbane research team has made a major advance in the fundamental understanding of how the embryo grows in the crucial first few days of life.
A combined University of Queensland and Queensland University of Technology (QUT) team has found evidence further challenging the widely-held view that the growth hormone (GH) is activated only after birth.
The researchers have suggested a role for GH in development of the embryo as from the time of fertilisation, contrary to the conventional view that embryonic and foetal growth occur independently of GH.
The findings, which have attracted intense international interest, have been published in the Proceedings of the USA National Academy of Science and were communicated by the chair of the Medical Research Council of Canada, Professor Henry Friesen.
They have important medical and veterinary applications, for example, improving the viability of the developing egg and the success rate for in vitro fertilisation in humans and animals. The average Australian human in vitro success rate is only 10-12 percent, although the success rate is higher in other animals.
Manipulation of embryos of agriculturally valuable animals is a common reproductive technology aimed at rapidly improving the genetic characteristics of a flock or herd. In these cases, the interval during which the embryo is in vitro and disconnected from the maternal support is much longer. So development of optimal conditions for manipulating embryos in vitro to improve the potential for a manipulated embryo to survive to reproductive age is a high priority.
The work also may have applications in modulating embryonic growth rates to overcome foetal growth disorders caused by too rapid or too slow growth rates.
If foetal growth is too slow, a human or animal can be born small-for-gestational age and with increased risk for death. However, if growth is too rapid, the foetus can be born too large, presenting increased hazards for mother and child at birth.
Research team members involved in the latest discovery are University of Queensland PhD student Marie Pantaleon, Associate Professor Peter Kaye and Associate Professor Mike Waters of the University's Physiology and Pharmacology Department; Eliza Whiteside and Dr Mark Harvey of QUT's School of Life Sciences; and Dr Ross Barnard of the Co-operative Research Centre for Diagnostic Technologies at QUT.
The researchers have been studying the role of GH in early embryonic development, particularly the first few days of life before the embryo implants itself in the uterus, and before the mother is aware of its existence. The mother's placenta grows to nourish the embryo from the time of implantation, and later the embryo develops into a foetus.
Implantation is believed to be the most difficult stage of life, and failure of the embryo to implant is cited as the most common reason for loss of foetal viability.
Dr Kaye's team, which has a long-standing interest in cell signalling in early embryonic development, joined with Dr Waters' team which specialises in GH, a naturally-occurring substance produced by the brain's pituitary gland and which is required for normal growth postnatally.
The early embryonic physiology group had discovered some years ago that growth of very early embryos was regulated by insulin from day three of pregnancy, indicating that the maternal physiology was in communication with the embryo soon after conception.
Focus switched to GH, a key hormone promoting body growth after birth, as evidence that it also might be important in fetal growth began to accumulate. Dr Waters' group is also interested in GH receptors, which allow tissues to respond to blood-borne growth hormone, and in IGF1, a mediator of growth hormone.
Dr Waters said it had traditionally been believed that GH did not have a role in growth until after the baby's birth.
The researchers looked at the action of GH and whether it stimulated aspects of embryo growth. Using the mouse as a model, they demonstrated the presence of GH receptors in the early embryo before implantation, from the time of fertilised eggs (day one) to the formation of more complex embryonic structures known as blastocysts (day four).
The researchers used several tests to demonstrate that by day four these GH receptors were functional, raising the possibility that GH may be involved in early embryonic growth and development. GH was shown to affect cellular functions such as glucose uptake and protein synthesis by blastocysts. There was also evidence of expression by GH receptors, using monoclonal antibodies developed by Dr Waters. These findings were verified using the University of Queensland's sophisticated confocal laser scanning microscope.
'If the receptors are able to be activated, the question was, is there GH present to stimulate them - in the mother's oviduct fluid, or in the embryo,' Dr Waters said. 'It appears the embryo can use both sources.'
It was a novel finding that the embryo had the capacity to make and respond to its own growth signals.
'This work raises intriguing questions about the mode of possible GH action at this stage of development,' Dr Waters said.
The researchers believe these responses show that GH should be considered as an additional element in a complex and dynamic system in which embryo-maternal communications are important for the viability of the embryo.
In the 1980s, Dr Waters, Dr Barnard and others disproved the theory that the liver was the sole basis for normal body growth and demonstrated that the process of bone growth occurred directly in the bones. In a joint project with genetic engineering firm Genentech of San Francisco, they cloned growth hormone receptors for the first time in 1985.
As a result of this work it is now possible to identify dwarfs with no GH receptors, and who cannot possibly benefit from GH therapy, but who are able to respond to the GH mediator, IGF1.
In 1992 Dr Waters' team located growth hormone receptors in the foetus in the first trimester. They also located GH receptors for the first time within the brain, in teeth and the gut, and improved understanding of how growth hormone influences metabolism.
The current work refines earlier findings to indicate the presence of growth hormone receptors at an even earlier stage, before the embryo implants itself in the uterus.
The result is the culmination of more than 15 years' research by the separate teams, much of it supported by the National Health and Medical Research Council, and the Australian Research Council. Ms Pantaleon was supported by a University of Queensland Postgraduate Re-entry Research Scholarship.
For further information, contact Dr Kaye or Ms Pantaleon (telephone 07 3365 1072 email: kaye@plpk.uq.edu.au, or marie@plpk.uq.edu.au) or Dr Waters (telephone 07 3365 2607 m.waters@mailbox.uq.edu.au).
