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Co-adaptive evolution of brain and placenta - a template for foetal programming of adult phenotypes

Reference	BB/F001541/1
Principal Investigator / Supervisor	Professor Eric Keverne
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Zoology
Funding type	Research
Value (£)	313,637
Status	Completed
Type	Research Grant
Start date	01/09/2007
End date	31/08/2010
Duration	36 months

Abstract

As a consequence of viviparity the in-utero interaction which occurs between mother and foetus is unique to mammals. The placenta which is genetically foetal, serves to regulate maternal endocrinology and physiology in order to optimise transfer of resources to the foetus and at the same time ensure changes occur in the mothers behaviour to meet infant demands in the pre- and post-partum period. Interactions across mother-infant phenotypes involving the maternal hypothalamus, foetal placenta and developing foetal hypothalamus provide a template for co-adaptive selection pressures to operate. The evolutionary outcome of this linked co-adaptation is that offspring that have extracted 'good' maternal nurturing both pre- and post-natally would themselves be well provisioned for early reproduction and, in the case of the females, genetically predisposed towards good mothering when adult. Maternally imprinted genes which are paternally expressed have played a crucial role in this co-adaptive development of mother and offspring. Transgenerational interactions across maternal hypothalamus, foetal placenta and foetal hypothalamus, all regulated by the same imprinted haploid dominant allele not only provide a template for mother-infant co-adaptive evolution, but this template is also amenable to environmental perturbation of the kind on which foetal programming for adult behaviour and physiological homeostasis may depend. In this project, we will investigate the co-ordinated expression of key imprinted genes in the placenta and developing foetal hypothalamus at the time foetal energy requirements start to impose a substantial demand on mother. We will determine gene networks, their similarities and differences in the developing hypothalamus and placenta through perturbations to this network using mice with mutation of imprinted genes (Peg3). These are likely to be candidate networks for epigenetic dysregulation in foetal programming.

Summary

The links between gene and behaviour are multiple and complex and affymetric screens for gene expression often provide a wealth of data that is difficult to interpret. However, evolution has been conservative and the genome contains fewer genes than expected. It is therefore clear that a given gene may be employed in many different contexts. Imprinted genes (unique to mammals and not following the Mendelian rules of expression) are nearly all expressed in the developing placenta and a subset are also expressed in the developing brain. The placenta and brain are very different structures with very different functions, but in the pregnant mother there is a great deal of cross talk for ensuring provision of nutrients, activation of the birth process and priming of maternal care and nurturing. The control which the foetus has over its own destiny has required a substantial degree of co-adaptation between the brain and placenta. We believe, based on good evidence, that this co-adaptation has occurred during the simultaneous development of these two structures. The question then arises as to how the developing brain 'knows' what it needs to do when adult? Since the developing placenta has to interact with the adult brain then a given gene simultaneously expressed in both developing structures (placenta and foetal brain) are under constraint by the placental interaction with the mature brain. The placental therefore acts as an interface between the adult brain and the developing brain, and with imprinted genes the same allele which has developed the maternal brain is also instrumental in development of the foetal brain and placenta. The interacting networks regulated by such imprinted genes are therefore likely to be part of the same networks that are susceptible to epigenetic influences known to be important in foetal programming of adult behaviour .

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Ageing, Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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