{"doi":"10.1093/function/zqaf018","title":"Lentivirus-Mediated Trophoblast-Specific <i>Deptor</i> Knockdown Increases Transplacental System A and System L Amino Acid Transport and Fetal Growth in Mice","abstract":"Mechanistic target of rapamycin (mTOR) signaling is a positive regulator of human placental function including system A/L amino acid transport activity. 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.","journal":"Function","year":2025,"id":550366,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":813171,"name":"Owen R. Vaughan","orcid":"0000-0001-7537-3264","position":1,"is_corresponding":false},{"id":1082129,"name":"Kenneth Barentsen","orcid":null,"position":2,"is_corresponding":false},{"id":723720,"name":"Johann Urschitz","orcid":null,"position":3,"is_corresponding":false},{"id":228377,"name":"Theresa L. Powell","orcid":"0000-0001-7410-1080","position":4,"is_corresponding":false},{"id":320526,"name":"Thomas Jansson","orcid":"0000-0002-8123-9480","position":5,"is_corresponding":false},{"id":479463,"name":"Fredrick J. Rosario","orcid":"0000-0001-7282-7005","position":6,"is_corresponding":false},{"id":1022407,"name":"Avery C. Kramer","orcid":"0000-0002-7839-0606","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T02:54:16.596730Z","pmid":"40133007","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}