title: Cell cycle regulation and cytoskeletal remodelling are critical processes in the nutritional programming of embryonic development.
abstract: Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common "gatekeepers" which may drive nutritional programming.Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05). This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency.The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.
authors.affiliation: School of Biosciences, University of Nottingham, Sutton Bonington, Loughborough, United Kingdom. angelina.swali@nottingham.ac.uk
authors.forename: Angelina
authors.initials: A
authors.lastname: Swali
authors.forename: Sarah
authors.initials: S
authors.lastname: McMullen
authors.forename: Helen
authors.initials: H
authors.lastname: Hayes
authors.forename: Lorraine
authors.initials: L
authors.lastname: Gambling
authors.forename: Harry J
authors.initials: HJ
authors.lastname: McArdle
authors.forename: Simon C
authors.initials: SC
authors.lastname: Langley-Evans
mesh_terms: D000824:Animal Nutritional Physiological Phenomena / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018592:Cross-Over Studies; D003599:Cytoskeleton / Q000378:metabolism*; D004032:Diet; D004044:Dietary Proteins / Q000008:administration & dosage; D015180:Electrophoresis, Gel, Two-Dimensional; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D007501:Iron / Q000008:administration & dosage; D000090463:Iron Deficiencies; D007668:Kidney / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000503:physiopathology; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004044:Dietary Proteins; D007501:Iron