{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T22:19:38Z","timestamp":1783549178408,"version":"3.55.0"},"reference-count":80,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD068370"],"award-info":[{"award-number":["HD068370"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD092716"],"award-info":[{"award-number":["HD092716"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Silencing of DEP\u2010domain containing mTOR\u2010interacting protein (DEPTOR), an endogenous inhibitor of the mammalian target of rapamycin (mTOR) pathway, increases mTOR signaling and System A\/L amino acid transport activity in cultured primary human trophoblast cells. However, there is no evidence supporting the regulatory role of DEPTOR signaling in placental function in\u00a0vivo. We hypothesized that trophoblast\u2010specific <jats:italic>Deptor<\/jats:italic> knockdown <jats:sup>(<jats:italic>KD<\/jats:italic>)<\/jats:sup> in mice increases trophoblast mTOR signaling, amino acid transport, and enhances fetal growth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated trophoblast\u2010specific <jats:italic>Deptor<\/jats:italic><jats:sup><jats:italic>KD<\/jats:italic><\/jats:sup> transgenic mice, and at embryonic day 18.5, placentas were analyzed to confirm knockdown efficiency, specificity, and mTOR signaling pathway levels. Trophoblast plasma membrane (TPM) System A\/L amino acid transport expression and activity were also determined. We also examined the relationship between birthweight and DEPTOR protein levels in human placentas collected at term from appropriate for gestational age (AGA) and large for gestational age (LGA) pregnancies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Reducing trophoblast <jats:italic>Deptor<\/jats:italic> RNA levels increased placental mTOR signaling, System A\/L transporter expression\/activity, and fetal growth in mice. Similarly, human LGA placentas displayed decreased DEPTOR protein levels, inversely correlated to birthweight and BMI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first report showing that trophoblast\u2010specific <jats:italic>Deptor<\/jats:italic><jats:sup><jats:italic>KD<\/jats:italic><\/jats:sup> is sufficient to activate mTOR signaling, a master regulator of placental function, which increases the TPM System A and L amino acid transporter expression and activity. We also propose that <jats:italic>Deptor<\/jats:italic> expression is mechanistically linked to placental mTOR signaling and fetal growth. Furthermore, modulation of DEPTOR signaling may represent a promising approach to improve outcomes in pregnancies characterized by abnormal fetal growth.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.70012","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T21:12:35Z","timestamp":1741727555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Trophoblast\u2010specific Deptor knockdown enhances trophoblast nutrient transport and fetal growth in mice"],"prefix":"10.1111","volume":"241","author":[{"given":"Lance G. A.","family":"Nunes","sequence":"first","affiliation":[{"name":"Institute for Biogenesis University of Hawaii, John A Burns School of Medicine  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo B.","family":"Weingrill","sequence":"additional","affiliation":[{"name":"Institute for Biogenesis University of Hawaii, John A Burns School of Medicine  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam Blessen J.","family":"Fredrick","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology University of Colorado  Denver Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Lorca","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Colorado, Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Men\u2010Jean","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Hawaii, John A Burns School of Medicine  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaikh M.","family":"Atif","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Colorado, Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Chicco","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Colorado State University  Fort Collins Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7282-7005","authenticated-orcid":false,"given":"Fredrick J.","family":"Rosario","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Colorado, Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Urschitz","sequence":"additional","affiliation":[{"name":"Institute for Biogenesis University of Hawaii, John A Burns School of Medicine  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f4539"},{"issue":"6","key":"e_1_2_10_3_1","article-title":"Risk factors associated with intrauterine growth restriction: a case\u2010control study","volume":"15","author":"Dapkekar P","year":"2023","journal-title":"Cureus"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.1991.tb15393.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.1992.tb13719.x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1993.tb12854.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0950115"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc05-2401"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00215-7"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.860110"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25706-z"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/GRF.0b013e3182993a2e"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1017\/S2040174412000529"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1275515"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2007.05.002"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.104141"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(03)00179-9"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.51.7.2214"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199810000-00011"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2013.83"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2008.07.001"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(03)00172-6"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1053\/plac.2002.0826"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu13082892"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.116.141085"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-1153"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.550004"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-021-00247-4"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-003-1117-9"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0199-y"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242015215"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2017092118"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20190794"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.238014"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep31705"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36265-8"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24087273"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20201050"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1515484112"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-016-0759-3"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.071193"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20150511"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2667"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.03.046"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.03.003"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.02.005"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1216473109"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20563"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2018.04.012"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301893"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.4161\/mge.25167"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12030277"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.11.020"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101170"},{"key":"e_1_2_10_56_1","doi-asserted-by":"crossref","unstructured":"RosarioFJ UrschitzJ RazavyH ElstonM TheresaPL JanssonT.PiggyBac Transposase Mediated Inducible Trophoblast\u2010Specific Knockdown of Mechanistic Target of Rapamycin in Mice Decreases Placental Nutrient Transport and Inhibits Fetal Growth.2024. bioRxiv. 2024.2002.2020.581180.","DOI":"10.1101\/2024.02.20.581180"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.113.116905"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.8.4575"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20150554"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.129676"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2017.10.001"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.repbio.2021.100503"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2018.10.017"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00356.2015"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037899"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.173013"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.1996.tb09914.x"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.156133"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1602012113"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-18-0093"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.198622"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/oby.21165"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00070"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12399"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa049"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13741"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003674107"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2009.11.006"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20210575"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02977671"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20230490"}],"container-title":["Acta Physiologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.70012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,13]],"date-time":"2025-04-13T07:53:43Z","timestamp":1744530823000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apha.70012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,5]]},"references-count":80,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1111\/apha.70012"],"URL":"https:\/\/doi.org\/10.1111\/apha.70012","archive":["Portico"],"relation":{},"ISSN":["1748-1708","1748-1716"],"issn-type":[{"value":"1748-1708","type":"print"},{"value":"1748-1716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,5]]},"assertion":[{"value":"2024-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70012"}}