Dissecting an epigenetic process that extrinsically govern fetal size

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

In mammals, embryonic growth is finely tuned and the placenta provides sufficient support for optimal embryonic growth. Too little support will have an adverse effect as embryonic growth is restrained which can result in intrauterine growth restriction. Too much support is wasteful and uses up maternal resources needlessly. It is therefore critical that the fetus and the supporting structures are working in harmony. Imprinted genes, which are expressed in mammals from only one parental allele, play a key role in this process. We are investigating a group of imprinted genes that are located within a discrete chromosomal region that is regulated by a single imprinting centre. Any global change in the expression of these genes has catastrophic consequences on both embryonic development and placental growth. We have already identified one of these genes, Cdkn1c, as the major regulator of embryonic growth within this domain. Several other genes are expressed in the placenta and some have been shown to play a critical role in placental development. In this proposal, we will determine whether two of these genes, known as Phlda2 and Slc22a18, act synergistically with Cdkn1c to balance embryonic growth and placental function. This work is important in our understanding how the placenta functions for optimal health. Intriguingly, the genes we are working on are adjacent in the genome and by studying them we may learn more about the functional consequences of imprinting these genes and how this may have influenced the evolution of the mammalian placenta. Critically, we will also learn more about the consequences of deregulated expression of these genes on development and disease.

Technical Summary

We have previously shown that genetic loss of expression of one imprinted gene, Cdkn1c, initially provides a significant growth advantage to the embryo. However, this advantage is not maintained later in embryogenesis. In this proposal, we will test the hypothesis that at least one other imprinted gene sharing the same imprint control region as Cdkn1c is required to compliment the intrinsic growth advantage provided by imprinting Cdkn1c. We have identified two candidate genes that may perform this function: Phlda2, which encodes a rheostat for placental growth, and the adjacent gene Slc22a18, which encodes an organic cation transporter. In this proposal we aim to test our hypothesis by Characterising the developmental consequences of the combined alteration in Phlda2 and Slc22a18 in our existing transgenic model Genetically rescuing excess expression of Phlda2 to isolate the individual contribution of Slc22a18 and, by inference, also Phlda2 Performing a series of experiments to test the functional capacity of the Phlda2-deficient placenta This last objective will be achieved by providing a tetraploid Phlda2-deficient placenta to an embryo with an intrinsic growth advantage and characterising fetal growth. By using a Cdkn1c-deficient embryo, in addition to testing our hypothesis, we will also distinguish the phenotypic consequences of loss of Cdkn1c expression in the embryo from loss of expression in the placenta. This work will further establish the role of imprinting in the subtle interplay between the intrinsic potential of the embryo and functional capacity of the placenta required for optimal growth.

Publications


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Burton, Graham; Barker, David J. P.; Moffett, Ashley (University Of Cambridge); Thornburg, Kent (2010) The Placenta and Human Developmental Programming
Tunster SJ (2011) Fetal overgrowth in the Cdkn1c mouse model of Beckwith-Wiedemann syndrome. in Disease models & mechanisms
Tunster SJ (2011) BACs as tools for the study of genomic imprinting. in Journal of biomedicine & biotechnology
Tunster SJ (2010) The imprinted Phlda2 gene regulates extraembryonic energy stores. in Molecular and cellular biology
 
Description A fundamental biological question is 'What governs fetal size'. Growth potential is intrinsic to the embryo but recent data suggests that in mammals epigenetic processes extrinsic to the embryo determine whether this growth potential can be exploited. The hypothesis that we explored in this proposal was that imprinted genes work synergistically to enhance

fetal growth.



Using a combination of loss of function and loss of imprinting models, we identified a key role for Phlda2 in regulating ex
Exploitation Route These studies have provided direction for our future work exploring the role of imprinted gene dosage in the placenta in the programming of pregnancy adaptation for which we now have successfully been awarded funding (BB/J015156/1).

While not a direct aspect of the research, by providing insight into the origins of low birth weight, the work may have clinical relevance and may also lead to the development of diagnostic tools. This research furthered our basic understanding of the complex relationship between fetus, placenta and mother. In addition, the research may be of use in interpreting the origins of pregnancy complications in mammals, including humans
Sectors Healthcare
 
Description While not a direct aspect of the research, by providing insight into the origins of low birth weight, the work may have clinical relevance and may also lead to the development of diagnostic tools. This research furthered our basic understanding of the complex relationship between fetus, placenta and mother. In addition, the research may be of use in interpreting the origins of pregnancy complications in mammals, including humans. Our work may have impact in enhancing of quality of life. We have consequently begun to engage with clinicians and healthcare workers to communicate the results of our work. We have also engaged with the public to disseminate our research findings.
First Year Of Impact 2010
Sector Education
Impact Types Societal
 
Description Response mode
Amount £475,990 (GBP)
Funding ID BB/J015156/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2012 
End 08/2015
 
Title Transgenic model 
Description Transgenic model of two-fold elevated Phlda2 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact In addition to publications, meeting presentations and public/healthcare presentation, findings from this new model underpinned applications for a PhD studentship (internal funding) and two external grants (BBSRC J015156) and MRC grant (letter pending). 
 
Description Engaging with public 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Engaged children and parents in discussions

?
Year(s) Of Engagement Activity 2011