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Placental mTOR signaling is inhibited in fetal growth restriction (FGR) and activated in fetal overgrowth in women; however, the causes of these changes in placental mTOR signaling are unknown. DEP (Dishevelled, Egl-10, Pleckstrin) domain containing mTOR-interacting protein (DEPTOR) is an endogenous inhibitor of mTOR. We tested the hypothesis that trophoblast-specific Deptor knockdown activates placental mTOR signaling and amino acid transport and causes fetal overgrowth. Using lentiviral transduction of blastocyst trophectoderm with a small hairpin RNA, we achieved 47% knockdown of placental Deptor mRNA expression, without altering fetal Deptor mRNA expression. Trophoblast-specific Deptor knockdown activated placental mTORC1 and mTORC2 signaling and increased trophoblast plasma membrane (TPM) LAT1 and SNAT2 protein abundance, and TPM system L and A transporter activity. In addition, Deptor knockdown increased in vivo transplacental system A and L amino acid transport and stimulated placental and fetal growth. In human FGR, placental DEPTOR protein expression was higher and negatively correlated with birth weight and microvillus plasma membrane system A activity. In conclusion, we provide mechanistic evidence that DEPTOR regulates placental mTOR signaling and amino acid transport and fetal growth in vivo. We speculate that modulation of placental DEPTOR is a promising target for intervention in pregnancies characterized by abnormal placental function and fetal growth.<\/jats:p>","DOI":"10.1093\/function\/zqaf018","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T17:03:01Z","timestamp":1744477381000},"source":"Crossref","is-referenced-by-count":4,"title":["Lentivirus-Mediated Trophoblast-Specific\n                    <i>Deptor<\/i>\n                    Knockdown Increases Transplacental System A and System L Amino Acid Transport and Fetal Growth in Mice"],"prefix":"10.1152","volume":"6","author":[{"given":"Avery","family":"Kramer","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen R","family":"Vaughan","sequence":"additional","affiliation":[{"name":"EGA Institute for Women\u2019s Health, University College London , London, WC1E 6HX ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Barentsen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8894-5716","authenticated-orcid":false,"given":"Johann","family":"Urschitz","sequence":"additional","affiliation":[{"name":"Institute for Biogenesis Research, University of Hawaii , Honolulu, HI 96822 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa L","family":"Powell","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus , Aurora, CO 80045 ,","place":["USA"]},{"name":"Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-9480","authenticated-orcid":false,"given":"Thomas","family":"Jansson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus , Aurora, CO 80045 ,","place":["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, CO 80045 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