title: Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup.
abstract: Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk.
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom ; Department of Medical & Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Cowley
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom ; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Alastair S
authors.initials: AS
authors.lastname: Garfield
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Madon-Simon
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Marika
authors.initials: M
authors.lastname: Charalambous
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Clarkson
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Biomedical Sciences Building, Cardiff University, Cardiff, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Biomedical Sciences Building, Cardiff University, Cardiff, United Kingdom.
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.affiliation: Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine and Psychology, Cardiff University, Cardiff, United Kingdom.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Isles
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
authors.forename: Aled J
authors.initials: AJ
authors.lastname: Parry
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Carney
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Oakey
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
authors.forename: Kim
authors.initials: K
authors.lastname: Moorwood
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Wolf
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ward
mesh_terms: D000818:Animals; D049628:Body Size / Q000235:genetics*; D005260:Female; D051383:GRB10 Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D028884:Karyopherins / Q000502:physiology; D007774:Lactation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D000097606:Exportin 1 Protein
chemical_list: D051383:GRB10 Adaptor Protein; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D050799:STAT5 Transcription Factor; D000097606:Exportin 1 Protein; C495959:Grb10 protein, mouse