{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:20:31Z","timestamp":1778502031585,"version":"3.51.4"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.17124.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000}}],"reference-count":49,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"MRC National Institute for Medical Research","doi-asserted-by":"publisher","award":["MC_U117584237"],"award-info":[{"award-number":["MC_U117584237"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["104566"],"award-info":[{"award-number":["104566"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["218662"],"award-info":[{"award-number":["218662"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>\n                    <ns3:bold>Background:<\/ns3:bold>\n                    Maternal malnutrition can lead to fetal growth restriction. This is often associated with organ sparing and long-lasting physiological dysfunctions during adulthood, although the underlying mechanisms are not yet well understood.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods:<\/ns3:bold>\n                    Low protein (LP) dietary models in C57BL\/6J mice were used to investigate the proximal effects of maternal malnutrition on fetal organ weights and organ sparing at embryonic day 18.5 (E18.5).\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results:<\/ns3:bold>\n                    \u00a0Maternal 8% LP diet induced strikingly different degrees of fetal growth restriction in different animal facilities, but adjustment of dietary protein content allowed similar fetal body masses to be obtained. A maternal LP diet that restricted fetal body mass by 40% did not decrease fetal brain mass to the same extent, reflecting positive growth sparing of this organ. Under these conditions, fetal pancreas and liver mass decreased by 60-70%, indicative of negative organ sparing. A series of dietary swaps between LP and standard diets showed that the liver is capable of efficient catch-up growth from as late as E14.5 whereas, after E10.5, the pancreas is not.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions:<\/ns3:bold>\n                    This study highlights that the reproducibility of LP fetal growth restriction studies between laboratories can be improved by careful calibration of maternal dietary protein content. LP diets that induce 30-40% restriction of prenatal growth provide a good model for fetal organ sparing. For the liver, recovery of growth following protein restriction is efficient throughout fetal development but, for the pancreas, transient LP exposures spanning the progenitor expansion phase lead to an irreversible fetal growth deficit.\n                  <\/ns3:p>","DOI":"10.12688\/wellcomeopenres.17124.2","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T10:50:18Z","timestamp":1651661418000},"page":"218","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Quantification of fetal organ sparing in maternal low-protein dietary models"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7485-1161","authenticated-orcid":false,"given":"Patricia","family":"Serpente","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2194-7116","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9131-7956","authenticated-orcid":false,"given":"Eva","family":"Islimye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Hart-Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6875-6985","authenticated-orcid":false,"given":"Alex 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ischaemic heart disease in England and Wales.","volume":"1","author":"D Barker","year":"1986","journal-title":"Lancet."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"2225-2234","DOI":"10.1007\/s00125-018-4694-z","article-title":"Programming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice.","volume":"61","author":"L Berends","year":"2018","journal-title":"Diabetologia."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"R291-299","DOI":"10.1152\/ajpregu.90497.2008","article-title":"Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice.","volume":"297","author":"V Bol","year":"2009","journal-title":"Am J Physiol Regul Integr Comp Physiol."},{"key":"ref-36","doi-asserted-by":"publisher","first-page":"e21477","DOI":"10.1096\/fj.202002557RR","article-title":"Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.","volume":"35","author":"E Camm","year":"2021","journal-title":"FASEB J."},{"key":"ref-37","doi-asserted-by":"publisher","first-page":"83-92","DOI":"10.1677\/joe.1.06754","article-title":"Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific.","volume":"191","author":"A Chamson-Reig","year":"2006","journal-title":"J Endocrinol."},{"key":"ref-38","doi-asserted-by":"publisher","first-page":"109912","DOI":"10.1016\/j.celrep.2021.109912","article-title":"Fetal growth restriction impairs hippocampal neurogenesis and cognition via Tet1 in offspring.","volume":"37","author":"W Chen","year":"2021","journal-title":"Cell Rep."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"e4950","DOI":"10.1371\/journal.pone.0004950","article-title":"Maternal protein restriction affects postnatal growth and the expression of key proteins involved in lifespan regulation in mice.","volume":"4","author":"J Chen","year":"2009","journal-title":"PLoS One."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"373-384","DOI":"10.1042\/CS20100230","article-title":"Maternal protein restriction affects gene expression profiles in the kidney at weaning with implications for the regulation of renal function and lifespan.","volume":"119","author":"J Chen","year":"2010","journal-title":"Clin Sci (Lond)."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"729-735","DOI":"10.1016\/j.jnutbio.2015.01.008","article-title":"Maternal low-protein diet causes body weight loss in male, neonate Sprague-Dawley rats involving UCP-1-mediated thermogenesis.","volume":"26","author":"K Claycombe","year":"2015","journal-title":"J Nutr Biochem."},{"key":"ref-39","doi-asserted-by":"publisher","first-page":"16-22","DOI":"10.1203\/PDR.0b013e3181e17c90","article-title":"The effects of low protein during gestation on mouse pancreatic development and beta cell regeneration.","volume":"68","author":"A Cox","year":"2010","journal-title":"Pediatr Res."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"591-603","DOI":"10.1079\/bjn19960065","article-title":"Organ-selective growth in the offspring of protein-restricted mothers.","volume":"76","author":"M Desai","year":"1996","journal-title":"Br J Nutr."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"363-378","DOI":"10.1159\/000240430","article-title":"Vulnerability of developing brain. IX. The effect of nutritional growth retardation on the timing of the brain growth-spurt.","volume":"19","author":"J Dobbing","year":"1971","journal-title":"Biol Neonate."},{"key":"ref-40","doi-asserted-by":"publisher","first-page":"1118-1123","DOI":"10.1080\/00016340903214924","article-title":"Redistribution pattern of fetal liver circulation in intrauterine growth restriction.","volume":"88","author":"C Ebbing","year":"2009","journal-title":"Acta Obstet Gynecol Scand."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"2609","DOI":"10.3390\/nu13082609","article-title":"The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein.","volume":"13","author":"H Fang","year":"2021","journal-title":"Nutrients."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"730-738","DOI":"10.1002\/oby.21806","article-title":"Concentration-dependent linkage of dietary methionine restriction to the components of its metabolic phenotype.","volume":"25","author":"L Forney","year":"2017","journal-title":"Obesity (Silver Spring)."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"1215-1230","DOI":"10.1113\/JP271099","article-title":"The fetal brain sparing response to hypoxia: physiological mechanisms.","volume":"594","author":"D Giussani","year":"2016","journal-title":"J Physiol."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"E7398-E7407","DOI":"10.1073\/pnas.1721876115","article-title":"Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory.","volume":"115","author":"J Gould","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"215-265","DOI":"10.1159\/000239870","article-title":"Chronic Fetal Distress and Placental Insufficiency.","volume":"5","author":"P Gruenwald","year":"1963","journal-title":"Biol Neonat."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"5-20","DOI":"10.1093\/bmb\/60.1.5","article-title":"The thrifty phenotype hypothesis.","volume":"60","author":"C Hales","year":"2001","journal-title":"Br Med Bull."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"1027-1076","DOI":"10.1152\/physrev.00029.2013","article-title":"Early developmental conditioning of later health and disease: physiology or pathophysiology?","volume":"94","author":"M Hanson","year":"2014","journal-title":"Physiol Rev."},{"key":"ref-43","doi-asserted-by":"publisher","first-page":"37-45","DOI":"10.1042\/CS20030350","article-title":"Programming of defective rat pancreatic beta-cell function in offspring from mothers fed a low-protein diet during gestation and the suckling periods.","volume":"107","author":"W Heywood","year":"2004","journal-title":"Clin Sci (Lond)."},{"key":"ref-44","doi-asserted-by":"publisher","first-page":"100797","DOI":"10.1016\/j.yfrne.2019.100797","article-title":"Prenatal and postnatal contributions of the maternal microbiome on offspring programming.","volume":"55","author":"E Ja\u0161arevi\u0107","year":"2019","journal-title":"Front Neuroendocrinol."},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"605","DOI":"10.3390\/nu11030605","article-title":"Offspring of Mice Exposed to a Low-Protein Diet in Utero Demonstrate Changes in mTOR Signaling in Pancreatic Islets of Langerhans, Associated with Altered Glucagon and Insulin Expression and a Lower \u03b2-Cell Mass.","volume":"11","author":"R King","year":"2019","journal-title":"Nutrients."},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"965-974","DOI":"10.1016\/s0024-3205(99)00022-3","article-title":"Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat.","volume":"64","author":"S Langley-Evans","year":"1999","journal-title":"Life Sci."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"283-298","DOI":"10.1007\/BF00237714","article-title":"Long-term effects of postnatal undernutrition and maternal malnutrition on mouse cerebral cortex. I. Cellular densities, cortical volume and total numbers of cells.","volume":"37","author":"G Leuba","year":"1979","journal-title":"Exp Brain Res."},{"key":"ref-45","doi-asserted-by":"publisher","first-page":"447-453","DOI":"10.1016\/j.jpeds.2013.01.060","article-title":"Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults.","volume":"163","author":"G L\u00f8haugen","year":"2013","journal-title":"J Pediatr."},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"571-633","DOI":"10.1152\/physrev.00053.2003","article-title":"Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.","volume":"85","author":"I McMillen","year":"2005","journal-title":"Physiol Rev."},{"key":"ref-46","doi-asserted-by":"publisher","first-page":"424","DOI":"10.3390\/life12030424","article-title":"The Maternal-Fetal Gut Microbiota Axis: Physiological Changes, Dietary Influence, and Modulation Possibilities.","volume":"12","author":"E Miko","year":"2022","journal-title":"Life (Basel)."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"368-372","DOI":"10.1093\/jn\/108.3.368","article-title":"The effects of prenatal protein restriction on the developing mouse cerebrum.","volume":"108","author":"H Nehrich","year":"1978","journal-title":"J Nutr."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"411-412","DOI":"10.1038\/427411b","article-title":"Lifespan: catch-up growth and obesity in male mice.","volume":"427","author":"S Ozanne","year":"2004","journal-title":"Nature."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.","volume":"18","author":"N Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"ref-47","doi-asserted-by":"publisher","first-page":"4861-4873","DOI":"10.1210\/endo.140.10.7042","article-title":"A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II.","volume":"140","author":"J Petrik","year":"1999","journal-title":"Endocrinology."},{"key":"ref-48","doi-asserted-by":"publisher","first-page":"465-476","DOI":"10.1159\/000363696","article-title":"Synaptic development and neuronal myelination are altered with growth restriction in fetal guinea pigs.","volume":"36","author":"K Piorkowska","year":"2014","journal-title":"Dev Neurosci."},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"173-177","DOI":"10.1016\/s0140-6736(97)07244-9","article-title":"Glucose tolerance in adults after prenatal exposure to famine.","volume":"351","author":"A Ravelli","year":"1998","journal-title":"Lancet."},{"key":"ref-23","doi-asserted-by":"publisher","first-page":"257-261","DOI":"10.1038\/nmeth.1312","article-title":"Environmental standardization: cure or cause of poor reproducibility in animal experiments?","volume":"6","author":"S Richter","year":"2009","journal-title":"Nat Methods."},{"key":"ref-24","article-title":"Extended data for \"Quantification of fetal organ sparing in maternal low-protein dietary models\".","author":"P Serpente","year":"2021"},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"67-83","DOI":"10.4137\/CMPed.S40070","article-title":"Intrauterine Growth Restriction: Antenatal and Postnatal Aspects.","volume":"10","author":"D Sharma","year":"2016","journal-title":"Clin Med Insights Pediatr."},{"key":"ref-49","doi-asserted-by":"publisher","first-page":"107-118","DOI":"10.1159\/000243170","article-title":"Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas.","volume":"57","author":"A Snoeck","year":"1990","journal-title":"Biol Neonate."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"886-891","DOI":"10.1038\/nature05537","article-title":"Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver.","volume":"445","author":"B Stanger","year":"2007","journal-title":"Nature."},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"3528-3537","DOI":"10.1210\/en.2015-1424","article-title":"Coenzyme Q10 Prevents Insulin Signaling Dysregulation and Inflammation Prior to Development of Insulin Resistance in Male Offspring of a Rat Model of Poor Maternal Nutrition and Accelerated Postnatal Growth.","volume":"156","author":"J Tarry-Adkins","year":"2015","journal-title":"Endocrinology."},{"key":"ref-50","doi-asserted-by":"publisher","first-page":"S153-158","DOI":"10.1053\/plac.2002.0810","article-title":"Liver blood perfusion as a possible instrument for fetal growth regulation.","volume":"23 Suppl A","author":"M Tchirikov","year":"2002","journal-title":"Placenta."},{"key":"ref-28","doi-asserted-by":"publisher","first-page":"17-29; discussion 29-37","DOI":"10.1002\/9780470514047.ch3","article-title":"Fetal response to intrauterine stress.","volume":"156","author":"K Thornburg","year":"1991","journal-title":"Ciba Found Symp."},{"key":"ref-29","doi-asserted-by":"publisher","first-page":"299-306","DOI":"10.1095\/biolreprod.107.064220","article-title":"Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease.","volume":"78","author":"A Watkins","year":"2008","journal-title":"Biol Reprod."},{"key":"ref-30","doi-asserted-by":"publisher","first-page":"329-342","DOI":"10.1098\/rspb.1963.0051","article-title":"The Effect of Finite Periods of Undernutrition at Different Ages on the Composition and Subsequent Development of the Rat.","volume":"158","author":"E Widdowson","year":"1963","journal-title":"Proc R Soc Lond B Biol Sci."},{"key":"ref-31","doi-asserted-by":"publisher","first-page":"154-156","DOI":"10.1203\/00006450-197503000-00010","article-title":"A review: new thoughts on growth.","volume":"9","author":"E Widdowson","year":"1975","journal-title":"Pediatr Res."},{"key":"ref-32","doi-asserted-by":"publisher","first-page":"221-230","DOI":"10.1113\/jphysiol.2005.100313","article-title":"A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat.","volume":"571","author":"E Zambrano","year":"2006","journal-title":"J Physiol."},{"key":"ref-51","doi-asserted-by":"publisher","first-page":"296-306","DOI":"10.1002\/mbo3.328","article-title":"The programming effects of nutrition-induced catch-up growth on gut microbiota and metabolic diseases in adult mice.","volume":"5","author":"J Zheng","year":"2016","journal-title":"Microbiologyopen."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T11:25:17Z","timestamp":1653564317000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,4]]},"references-count":49,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.17124.2","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.19785.r50291","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.19785.r50291","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,4]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.19785.r50291, David J. Hill, St Joseph Health Care, Lawson Health Research Institute, ON, Canada, 19 May 2022, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2#referee-response-50291","order":0,"name":"referee-response-50291","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18915.r48186, Paula N. Gonzalez, Faculty of Natural Sciences and Museum, Anthropology Division, CONICET, National University of La Plata, La Plata, Argentina, 07 Feb 2022, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v1#referee-response-48186","order":1,"name":"referee-response-48186","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Alex Gould<\/b>; \n<i>Posted: 22 Apr 2022<\/i>; \n<i>The study by Serpente and co-authors showed a differential effect of maternal low protein diet during gestation on body and organ weight in a mouse model, with the brain positive spared and the liver and the pancreas more affected. The study also explored the critical windows for each organ during prenatal growth, confirming that the timing and extension of nutrient restriction induce different responses across organs.  In particular, the results suggest that the pancreas is more sensitive than the liver to short periods of maternal protein deprivation. Although the mechanisms of organ sparing were not examined, the authors suggest that the timing of cellular processes such as the early proliferation of progenitors in the pancreas could partly explain the narrower window for a catch-up of this organ compared to the liver.  The effect of the redistribution pattern of fetal circulation in IUGR also need to be discussed (e.g., Tchirikov et al., 2002; Ebbing et al., 2009)<\/i>  We thank the Reviewer for these useful comments and have now expanded the first paragraph of the Introduction to discuss the redistribution pattern of fetal circulation. This now includes the evidence from Tchirikov \n<i>et al<\/i>., 2002 and Ebbing \n<i>et al<\/i>., 2009 that hepatic blood flow during IUGR may be a causal contributing factor to the restricted growth of multiple organs. In response to both Reviewers comments, we have also cited many other new references to the Introduction and Discussion sections of our rather short initial manuscript in order to better represent the literature.  \n<i>Interestingly, the effect of an 8% protein diet differs between two animal facilities, which is associated with differences in the microbiome. A review of the literature on experimental models of nutrient restriction reveals variable and even some contradicting results, and this study provides one possible explanation for such differences that deserves further research. This finding is relevant not only for replicating controlled conditions in experimental designs but also for the implications for studying the effect of malnutrition in human populations.<\/i>  We thank the Reviewer for acknowledging that our finding of a very marked difference in the extent of&nbsp; IUGR between two animal facilities is interesting and deserves further research. Although it is beyond the scope of the present manuscript, identifying the underlying microbiota or other mechanistic basis for this will be important and, as the Reviewer says, may also have implications for human IUGR.&nbsp;  \n<i>A previous study with a similar design shows that the effect of low protein diets is not homogeneous across cell types or brain regions (Barbeito et al., 2019). Given the detailed analysis of critical windows performed in this study, it would be interesting to explore whether they induce different responses at the cell level beyond the effect on overall brain size.<\/i>  This is a very interesting point. The regional bias in brain sparing shown in the study that we had previously cited by Barbeito-Andres \n<i>et al.<\/i> 2019 is important and we have now expanded upon this specific point in the Discussion. This includes mentioning the finding by Barbeito-Andres \n<i>et al<\/i>. 2019 that the volume of the cerebral cortex is more highly spared from the effects of maternal protein restriction than that of the cerebellum. Although it is beyond the scope of our current paper, we will in future investigate in cellular and molecular detail how critical temporal windows of LP exposure impact embryonic neurogenesis in different regions of the brain.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-218\/v2#referee-comment-4969","order":2,"name":"referee-comment-4969","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by funding from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001088), the UK Medical Research Council (FC001088) and the Wellcome Trust (FC001088). It was also supported by an Investigator Award to APG from the Wellcome Trust (104566), a Sir Henry Wellcome postdoctoral fellowship to YZ (218662) and by funding from the MRC National Institute for Medical Research (MC_U117584237). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}