The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems
Open accessAbstract
The mammalian fetus is unique in its dependence during gestation on the supply of maternal nutrients through the placenta. Maternal supply and fetal demand for nutrients need to be fine tuned for healthy growth and development of the fetus along its genetic trajectory. An altered balance between supply and demand can lead to deviations from this trajectory with long-term consequences for health. We have previously shown that in a knockout lacking the imprinted placental-specific Igf2 transcript (P0), growth of the placenta is compromised from early gestation but fetal growth is normal until late gestation, suggesting functional adaptation of the placenta to meet the fetal demands. Here, we show that placental transport of glucose and amino acids are increased in the Igf2 P0 +/- null and that this up-regulation of transport occurs, at least in part, through increased expression of the transporter genes Slc2a3 and Slc38a4 , the imprinted member of the System A amino acid transporter gene family. Decreasing fetal demand genetically by removal of fetal Igf2 abolished up-regulation of both transport systems and reduced placental System A amino acid transport activity and expression of Slc38a2 in late gestation. Our results provide direct evidence that the placenta can respond to fetal demand signals through regulation of expression of specific placental transport systems. Thus, crosstalk between an imprinted growth demand gene ( Igf2 ) and placental supply transporter genes ( Slc38a4 , Slc38a2 , and Slc2a3 ) may be a component of the genetic control of nutrient supply and demand during mammalian development.
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“There is also evidence for inter-sibling competition for nutrients between mutant and wild type fetuses within mixed litters, which affects the size of the wild type pups (14, 104, 124).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [124]
In the citing paper
“Comparison of the placental-specific Igf2P0 with the complete Igf2 null mutant demonstrates clearly that the small placenta can become more efficient by increasing its nutrient transfer and transporter abundance when there is a maintained drive for growth by feto-placental tissues still expressing Igf2 (124, 125).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [124]
In the citing paper
“Certainly, upregulation of placental amino acid transport is maintained until D19 in mice with complete Igf2P0null litters but not in Igf2P0 mutants of dams with mixed litters of mutants and wild types, which have a greater total conceptus mass and, thus, demand for nutrients in late gestation (124, 495).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [124]
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BackgroundInfluentialSelf-citationImprinted Genes, Placental Development and Fetal Growth
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“It has been proposed that placenta could act as a nutrient sensor according to resources available in the maternal supply line (29) and, in return, could respond to fetal demands (30).”
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“…growth retardation of the placenta (Constância et al. 2002), in association with specific morphological abnormalities and up-regulation of system A transporter abundance and activity in the mutant relative to the wild-type placenta (Sibley et al. 2004; Constância et al. 2005; Coan et al. 2008).”
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“The increased expression of Igf2P0 in the placentas of CU individuals is interesting as Igf2P0 has been proposed to play a key role in matching placental solute transport to foetal demand [62–63], and may represent an adaptive placental response to support CU foetal growth.”
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“SLC38A4, a gene involved in cell proliferation, tissue growth [49], and the transport of arginine and lysine across the plasma membrane [72], has been reported as imprinted and paternally expressed in all tissues tested in mice [73], and as not imprinted in cattle [74].”
Backgroundda Rocha, S. T., Charalambous, M., Lin, S., Gutteridge, I., Ito, Y., Gray, D., Dean, W., & Ferguson‐Smith, A. C. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000392 · Cited by 106
“With the exception of studies on placental specific Igf2 [28,29], previous functional analyses of imprinted genes expressed in embryo and placenta have not been able to discern whether growth effects are intrinsic to the embryo or are secondary to placental function.”
ResultSelf-citationJayabalan, N., Nair, S., Nuzhat, Z., Rice, G. E., Zuñiga, F. A., Sobrevía, L., Leiva, A., Sanhueza, C., Gutiérrez, J., Lappas, M., et al. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00239 · Cited by 106
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“Indeed, the placenta can respond to fetal demand by increasing the expression and activity of transporter genes (Constancia et al., 2005, 2002; Sferruzzi-Perri, Sandovici, Constancia, & Fowden, 2017).”
BackgroundFetal Growth Restriction: Pathogenic Mechanisms
Maulik, D., Evans, J. F., & Ragolia, L. (2006) · Clinical Obstetrics & Gynecology · doi:10.1097/00003081-200606000-00005 · Cited by 103
“There is substantial evidence that IGF-II may have a significant role in modulating placental nutrient transfer.(20) Placental IGF-II deficiency may lead to decreased placental size and permeability, and upregulation of the transport mechanisms associated with increased active maternal to fetal transfer of amino acids.”
BackgroundReconciling the nutritional and glucocorticoid hypotheses of fetal programming
Cottrell, E. C., Holmes, M. C., Livingstone, D. E., Kenyon, C. J., & Seckl, J. R. (2012) · The FASEB Journal · doi:10.1096/fj.12-203489 · Cited by 102
Higgins, J., Vaughan, O. R., de Liger, E. F., Fowden, A. L., & Sferruzzi-Perri, A. N. (2015) · The Journal of Physiology · doi:10.1113/jp271057 · Cited by 104
“Previous studies have shown that the Igf2 gene is essential for placental adaptation to undernutrition in late gestation and influences placental vascularity, barrier thickness and nutrient transport during normal development (Constancia et al. 2005; Coan et al. 2008, 2010; Sferruzzi-Perri et al. 2011).”
BackgroundResultSelf-citationMaternally-inherited Grb10 reduces placental size and efficiency
Charalambous, M., Cowley, M., Geoghegan, F., Smith, F. M., Radford, E. J., Marlow, B. P., Graham, C. F., Hurst, L. D., & Ward, A. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2009.10.011 · Cited by 101
The Human Placental MethylomePreprint
Robinson, W. P., & Price, E. M. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a023044 · Cited by 107
“In the last half of pregnancy, the placenta also shows changes in gene expression in response to the increasing demands of the fetus for nutrients (Constancia et al. 2005).”
Coan, P. M., Fowden, A. L., Constância, M., Ferguson‐Smith, A. C., Burton, G. J., & Sibley, C. P. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.157313 · Cited by 100
“The complete Igf2null+/− placenta supported less fetus per gram weight and, by the end of gestation, transferred less methyl-aminoisobutyric acid (MeAIB) per gram of placenta than its wild-type littermate in contrast to the Igf2P0+/− placenta (Constancia et al. 2005).”
BackgroundResultInfluentialSelf-citationPlacental adaptations supporting fetal growth during normal and adverse gestational environments
Sferruzzi-Perri, A. N., López‐Tello, J., & Salazar‐Petres, E. (2022) · Experimental Physiology · doi:10.1113/ep090442 · Cited by 105
Lee, K. L., Lim, S. K., Orlov, Y. L., Yit, L. Y., Yang, H. H., Ang, L. T., Poellinger, L., & Lim, B. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002130 · Cited by 95
“is an imprinted gene that modulates nutrient supply between the placenta and fetus”
BackgroundSibley, C. P., Brownbill, P., Dilworth, M. R., & Glazier, J. D. (2010) · Placenta · doi:10.1016/j.placenta.2009.12.020 · Cited by 95
Self-citationChen, S., Sun, F.-Z., Huang, X.-Y., Wang, X., Tang, N., Zhu, B., & Li, B. (2015) · Scientific Reports · doi:10.1038/srep10596 · Cited by 94
Review: Placenta, evolution and lifelong health
Lewis, R. M., Cleal, J. K., & Hanson, M. A. (2011) · Placenta · doi:10.1016/j.placenta.2011.12.003 · Cited by 91
Understanding placental nutrient transfer – why bother? New biomarkers of fetal growth
Sibley, C. P. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.172403 · Cited by 92
Self-citationIntrauterine calorie restriction affects placental DNA methylation and gene expression
Chen, P., Ganguly, A., Rubbi, L., Orozco, L. D., Morselli, M., Ashraf, D. C., Jaroszewicz, A., Feng, S., Jacobsen, S. E., Nakano, A., et al. (2013) · Physiological Genomics · doi:10.1152/physiolgenomics.00034.2013 · Cited by 91
Unearthing the Roles of Imprinted Genes in the Placenta
Bressan, F. F., De, T. H. C., Perecin, F., Lopes, F. L., Ambrósio, C. E., Meirelles, F. V., & Miglino, M. (2009) · Placenta · doi:10.1016/j.placenta.2009.07.007 · Cited by 94
Desforges, M., Mynett, K. J., Jones, R. L., Greenwood, S. L., Westwood, M., Sibley, C. P., & Glazier, J. D. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.161331 · Cited by 88
“2004), reduced placental system A activity is specifically associated with altered Slc38a4 expression (Constancia et al. 2005).”
BackgroundInfluentialSelf-citationKamei, H., Ding, Y., Kajimura, S., Wells, M. B., Chiang, P., & Duan, C. (2011) · Development · doi:10.1242/dev.056853 · Cited by 84
“Studies using various knockout mice suggest that the imprinted expression of Igf2 regulates fetal growth by coordinating the balance between placental nutrient/calcium supply and fetal demand (Constancia et al., 2002; Constancia et al., 2005; Dilworth et al., 2010).”
BackgroundHarris, L. K., Crocker, I. P., Baker, P. N., Aplin, J., & Westwood, M. (2010) · Biology of Reproduction · doi:10.1095/biolreprod.110.088195 · Cited by 96
“Igf1-null mice weigh 40% less than wild-type pups [1, 2], and ablation of Igf2 leads to concurrent fetal and placental growth restriction [3–5].”
BackgroundCleaton, M. A. M., Edwards, C. A., & Ferguson‐Smith, A. C. (2014) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153441 · Cited by 91
Self-citationDilworth, M., Kusinski, L. C., Cowley, E. J., Ward, B. S., Husain, S. M., Constância, M., Sibley, C. P., & Glazier, J. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911710107 · Cited by 85
“This finding confirms previous observations that P0 mice demonstrate growth restriction toward term following a significant reduction in placental weight that, according to previous reports, occurs earlier, at around E14 (8, 9).”
BackgroundResultSelf-citationCushing’s syndrome, glucocorticoids and the kidney
Smets, P. M. Y., Meyer, E., Maddens, B., & Daminet, S. (2010) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2010.07.004 · Cited by 90
Hormonal and nutritional drivers of intrauterine growth
Sferruzzi-Perri, A. N., Vaughan, O. R., Forhead, A. J., & Fowden, A. L. (2013) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32835e3643 · Cited by 82
Self-citationPankevich, D. E., Mueller, B. R., Brockel, B. J., & Bale, T. L. (2009) · Physiology & Behavior · doi:10.1016/j.physbeh.2009.04.015 · Cited by 84
DNA Methylation Causes Predominant Maternal Controls of Plant Embryo Growth
FitzGerald, J., Luo, M., Chaudhury, A., & Berger, F. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002298 · Cited by 81
“However some results also suggest a predominant maternal control of placental and embryo growth [30–32].”
Drake, A. J., Liu, L., Kerrigan, D., Meehan, R. R., & Seckl, J. R. (2011) · Epigenetics · doi:10.4161/epi.6.11.17942 · Cited by 81
Does the fetal genotype affect maternal physiology during pregnancy?
Petry, C. J., Ong, K. K., & Dunger, D. B. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.07.007 · Cited by 78
Placental glycogen stores and fetal growth: insights from genetic mouse models
Tunster, S. J., Watson, E. D., Fowden, A. L., & Burton, G. J. (2020) · Reproduction · doi:10.1530/rep-20-0007 · Cited by 84
Self-citationPlacental Mitochondrial Function and Dysfunction in Preeclampsia
Jahan, F., Vasam, G., Green, A. E., Bainbridge, S. A., & Menzies, K. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044177 · Cited by 81
Gao, H., Wu, G., Spencer, T. E., Johnson, G. A., & Bazer, F. W. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.108.075440 · Cited by 77
“In placenta, the crosstalk between IGF2, also a paternally imprinted gene, and SLC38A4 may affect genetic control of nutrient supply and demand during development [31].”
BackgroundMaternal corticosterone regulates nutrient allocation to fetal growth in mice
Vaughan, O. R., Sferruzzi‐Perri, A. N., & Fowden, A. L. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.239426 · Cited by 75
“The SNATs are transcribed from three genes, Slc38a1, Slc38a2 and Slc38a4, all of which are expressed in rodent and human placenta (Constancia et al. 2005; Desforges et al. 2006).”
BackgroundSelf-citationRoberts, C. T., Owens, J. A., & Sferruzzi-Perri, A. N. (2008) · Placenta · doi:10.1016/j.placenta.2007.12.002 · Cited by 74
Placental programming of anxiety in adulthood revealed by Igf2-null models
Mikaelsson, M. A., Constância, M., Dent, C. L., Wilkinson, L. S., & Humby, T. (2013) · Nature Communications · doi:10.1038/ncomms3311 · Cited by 75
Self-citationMühlhäusler, B. S., Hancock, S. N., Bloomfield, F. H., & Harding, R. (2011) · Pediatric Research · doi:10.1203/pdr.0b013e31821f6cfd · Cited by 73
Fauque, P., Ripoche, M., Tost, J., Journot, L., Gabory, A., Busato, F., Digarcher, A. L., Mondon, F., Gut, I. G., Jouannet, P., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq059 · Cited by 73
“Finally, the paternally expressed Slc38a4 gene (located on chromosome 15) is imprinted in the placenta only and encodes a system A amino acid transporter (49).”
BackgroundSferruzzi-Perri, A. N., López‐Tello, J., Fowden, A. L., & Constância, M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602012113 · Cited by 76
“seen when the fetal demand for maternal resources exceeds the supply capacity of the placenta following deletion of the Slc2a3 glucose transporter gene, in naturally small placentas within litters and when placental growth is impaired by a deficiency in the Lz-specific Igf2 transcript or the 11-β hydroxysteroid dehydr…”
BackgroundSelf-citationFletcher, C., Roberts, C. T., Hartwich, K. M., Walker, S., & McMillen, I. C. (2007) · Reproduction · doi:10.1530/rep.1.01203 · Cited by 70
“When the placental specific IGF-II P0 promoter is ablated placental growth restriction occurs, followed by fetal growth restriction and there are also associated changes in the functional transfer capacity of the placenta (Constancia et al. 2002, 2005, Sibley et al. 2004).”
BackgroundLarson, K., Bundy, A. N., & Roemmich, J. N. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108373 · Cited by 75
Dietary composition programmes placental phenotype in mice
Coan, P. M., Vaughan, O. R., McCarthy, J., Mactier, C., Burton, G. J., Constância, M., & Fowden, A. L. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.208629 · Cited by 67
“Expression of placental growth regulatory genes The increased placental weight, particularly in the C9 group, may be due, in part, to the enhanced placental expression of the Igf2 gene known to be important in stimulating placental growth (Constancia et al. 2002, 2005).”
BackgroundSelf-citationChassen, S. S., & Jansson, T. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.12.024 · Cited by 72
Metadata
- Authors
- Constância, M., Angiolini, E., Sandovici, I., Smith, P., Smith, R., Kelsey, G., Dean, W., Ferguson-Smith, A., Sibley, C. P., Reik, W., & Fowden, A.
- Affiliations
- Babraham Institute (GB)
- Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, United Kingdom; Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, United Kingdom; Division of Human Development, Medical School, University of Manchester, St. Mary's Hospital, Manchester M13 0JH, United Kingdom; and Department of Physiology, University of Cambridge, Cambridge CB2 3EG, United Kingdom
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-12-19
- Volume
- 102
- Issue
- 52
- Pages
- 19219-19224
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1316882
- OpenAlex
- W2155091020
- Cited by
- 323
- References
- 34
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 13 · 2020: 17 · 2019: 15 · 2018: 17 · 2017: 12 · 2016: 20 · 2015: 20 · 2014: 16 · 2013: 25 · 2012: 26
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BBS/E/B/0000S119, BB/B50118X/1, S18929, S18928)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- insulin-like growth factor II, genomic imprinting, placental nutrient transport, glucose transport, amino acid transport, GLUT3, SLC38A4, SLC38A2, system A, placental development, fetal growth, mice
- MeSH terms
- Alleles, Animals, Biological Transport, Female, Fetus, Genotype, Glucose, Insulin-Like Growth Factor II, Lac Operon, Mice, Inbred C57BL, Models, Genetic, Mutation, Placenta, Proteins, RNA, Messenger, Time Factors, Up-Regulation, Gene Deletion, Genomic Imprinting, Transgenes, Membrane Transport Proteins, Amino Acid Transport Systems, Amino Acid Transport System A, Glucose Transport Proteins, Facilitative, Glucose Transporter Type 3, Mice
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