{"id":"ac5cb310-b73c-5be9-8acf-71a30fd5bc35","stable_key":"3c852f36-7951-5fd9-9013-d771a8d16d8a:va-repro-rar-necessity-model","predicate":"proposed_required_for","statement":"The 2006 study inferred that RAR signaling is required for fetal ovarian Stra8 induction after BMS-204493 suppressed its expression.","claim_class":"hypothesis_link","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"6779dc8b-a8c0-55a6-9f0a-7fb73e136f98","mechanism_event_label":"An early drug experiment supported a requirement later challenged by genetics.","subject":{"id":"0453bf0c-3c7c-5275-9b9e-8d7f01613b51","slug":"rar-family","display_name":"Retinoic acid receptor family","entity_type_key":"protein_family"},"object":{"id":"6e6d852f-648d-5e5b-82a8-5a02fa77b14b","slug":"mouse-stra8-expression","display_name":"Mouse Stra8 expression","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"6779dc8b-a8c0-55a6-9f0a-7fb73e136f98","stable_key":"3c852f36-7951-5fd9-9013-d771a8d16d8a:va-repro-rar-necessity-model-event","event_type":"biochemical_relationship","label":"An early drug experiment supported a requirement later challenged by genetics.","description":"The 2006 study inferred that RAR signaling is required for fetal ovarian Stra8 induction after BMS-204493 suppressed its expression.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"bd32c9ac-cf73-589b-b0f5-7ad904b8d0fc","slug":"bms-204493","display_name":"BMS-204493","entity_type_key":"small_molecule"},"role":"experimental_antagonist","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"05487b29-8c59-5af8-83cf-cf9c79c5ecb8","slug":"all-trans-retinoic-acid","display_name":"All-trans-retinoic acid","entity_type_key":"small_molecule"},"role":"proposed_inducer","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"0453bf0c-3c7c-5275-9b9e-8d7f01613b51","slug":"rar-family","display_name":"Retinoic acid receptor family","entity_type_key":"protein_family"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"6e6d852f-648d-5e5b-82a8-5a02fa77b14b","slug":"mouse-stra8-expression","display_name":"Mouse Stra8 expression","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Pharmacologic model inference","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"E11.5 ovaries; 5 micromolar BMS-204493 for 2 days.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Disputed necessity inference; receptor repression differs from receptor deletion.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-a","display_name":"Vitamin A","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Mus musculus","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"An early drug experiment supported a requirement later challenged by genetics.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"fetal ovary","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"2552a1fc-8d71-5b5f-97a5-fc5e13f3e342","evidence_kind":"source_excerpt","locator":"Lines 187-198","start_line":187,"end_line":198,"excerpt":"### va-repro-rar-necessity-model\nThe 2006 study inferred that RAR signaling is required for fetal ovarian Stra8 induction after BMS-204493 suppressed its expression.\nCondition category: normal\nnutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: An early drug experiment supported a requirement later challenged by genetics.\norganism: Mus musculus\ntissue_or_cell_type: fetal ovary\nexperimental_model: Pharmacologic model inference\nlimitations: Disputed necessity inference; receptor repression differs from receptor deletion.\nexposure: E11.5 ovaries; 5 micromolar BMS-204493 for 2 days.\ncross_nutrient: false\n[koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103","model_system":"Pharmacologic model inference","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"83131a07-353f-5301-9ce6-50754c194952","stable_key":"import-3c852f36-7951-5fd9-9013-d771a8d16d8a","title":"Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"559cb4dc3f59519ecb0bc455dbcc73346fbf8e0c51e133f455781f51e4ed07ab","revision_id":"225fe4da-2d21-5c19-a92c-80a5f3cac8cb","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"180fff6e-8ce4-5314-8218-56e35543ba46","title":"Is RAR signaling obligatory for fetal ovarian meiotic entry?","kind":"contradiction","status":"open","why":"The 2006 pharmacologic study explicitly inferred an obligatory RAR-to-Stra8 trigger. The 2020 all-RAR genetic study explicitly disputed that necessity model after observing meiotic progression and functional oocytes.","resolution":"Unresolved at the broad physiological-model level. Keep the necessity inference labeled as hypothesis: inverse-agonist receptor repression is not equivalent to receptor deletion. The newer genetic results constrain universal necessity claims; timing, residual signaling and alternative triggers remain distinct questions. The 2021 endogenous promoter mutations independently support an RA-responsive contribution to optimal Stra8 expression without resolving obligatory ligand/receptor necessity. This selected literature set is not an exhaustive review of later work and does not negate adult or postnatal male vitamin A requirements.","created_at":"2026-09-17 13:14:53","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/180fff6e-8ce4-5314-8218-56e35543ba46","sides":[{"conflict_id":"180fff6e-8ce4-5314-8218-56e35543ba46","ordinal":0,"label":"Pharmacologic evidence interpreted as obligatory RAR signaling","revision_id":"225fe4da-2d21-5c19-a92c-80a5f3cac8cb","start_line":187,"end_line":198,"quote":"### va-repro-rar-necessity-model\nThe 2006 study inferred that RAR signaling is required for fetal ovarian Stra8 induction after BMS-204493 suppressed its expression.\nCondition category: normal\nnutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: An early drug experiment supported a requirement later challenged by genetics.\norganism: Mus musculus\ntissue_or_cell_type: fetal ovary\nexperimental_model: Pharmacologic model inference\nlimitations: Disputed necessity inference; receptor repression differs from receptor deletion.\nexposure: E11.5 ovaries; 5 micromolar BMS-204493 for 2 days.\ncross_nutrient: false\n[koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103","source_key":"import-3c852f36-7951-5fd9-9013-d771a8d16d8a","source_title":"Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17)","claim_ids":["ac5cb310-b73c-5be9-8acf-71a30fd5bc35"]},{"conflict_id":"180fff6e-8ce4-5314-8218-56e35543ba46","ordinal":1,"label":"Timed all-RAR deletion permitted meiotic progression","revision_id":"225fe4da-2d21-5c19-a92c-80a5f3cac8cb","start_line":304,"end_line":315,"quote":"### va-repro-rar-null-ovarian-meiosis\nFetal ovarian germ cells lacking all RARs expressed meiotic markers and reached zygotene, challenging an obligatory RAR trigger.\nCondition category: machinery_impairment\nnutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: The tested fetal ovarian program progressed without the RA receptors.\norganism: Mus musculus\ntissue_or_cell_type: fetal ovary\nexperimental_model: Timed receptor deletion with excision reporter\nlimitations: Does not test dietary vitamin A deprivation or every possible RAR-independent action.\nexposure: Tamoxifen induction at E9.5; meiosis assessed at E15.5.\ncross_nutrient: false\n[vernet2020] Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. (2020). https://pubmed.ncbi.nlm.nih.gov/32917583/ DOI: 10.1126/sciadv.aaz1139","source_key":"import-3c852f36-7951-5fd9-9013-d771a8d16d8a","source_title":"Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17)","claim_ids":["3637ec94-6984-50c8-ae03-880c0cd51876"]},{"conflict_id":"180fff6e-8ce4-5314-8218-56e35543ba46","ordinal":2,"label":"Later promoter genetics supports a contribution without settling obligatory RA necessity","revision_id":"225fe4da-2d21-5c19-a92c-80a5f3cac8cb","start_line":395,"end_line":406,"quote":"### va-repro-stra8-rare-mutations\nTargeted mutation of Stra8 RA-response elements reduced its expression in fetal mouse ovaries.\nCondition category: machinery_impairment\nnutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Later genetic promoter tests confirmed a contribution from RA-responsive DNA elements.\norganism: Mus musculus\ntissue_or_cell_type: fetal ovarian germ cells\nexperimental_model: CRISPR/Cas9 cis-regulatory mutation\nlimitations: Reduced optimal expression does not establish complete loss of expression or prove an obligatory RA trigger for all ovarian meiosis.\nexposure: RARE1 and RARE3 mutated singly or together; endogenous Stra8 expression assessed in vivo.\ncross_nutrient: false\n[feng2021] Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. (2021). https://pubmed.ncbi.nlm.nih.gov/33574039/ DOI: 10.1242/dev.194977","source_key":"import-3c852f36-7951-5fd9-9013-d771a8d16d8a","source_title":"Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17)","claim_ids":["57858073-f34c-5418-a3cc-91acf4ae78b4"]}]}],"corrections":[],"research":null}