{"doi":"10.1002/dvdy.20128","title":"<i>Raldh2</i> expression in optic vesicle generates a retinoic acid signal needed for invagination of retina during optic cup formation","abstract":"<jats:title>Abstract</jats:title><jats:p>Three retinaldehyde dehydrogenase genes (<jats:italic>Raldh1</jats:italic>, <jats:italic>Raldh2</jats:italic>, and <jats:italic>Raldh3</jats:italic>) expressed in unique spatiotemporal patterns may control synthesis of retinoic acid (RA) needed for retina development. However, previous studies indicate that retina formation still proceeds normally in <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup> mouse embryos lacking RA synthesis in the dorsal neural retina at the optic cup stage. Here, we demonstrate that <jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> embryos lacking RA synthesis in the optic vesicle exhibit a failure in retina invagination needed to develop an optic cup. This was also observed in <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup>:<jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> double mutants, which develop similarly. Both mutants retain RA activity in the lens placode associated with <jats:italic>Raldh3</jats:italic> expression, but this RA activity is insufficient to induce optic cup formation. Maternal RA administration at the optic vesicle stage rescues optic cup formation in <jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> and <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup>:<jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> embryos, demonstrating that <jats:italic>Raldh1</jats:italic> is not required during rescue of optic cup development. The optic cup of rescued <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup>:<jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> embryos exhibits normal RA activity and this is associated with <jats:italic>Raldh3</jats:italic> expression in the retina and lens. Thus, RA signaling initiates in the optic vesicle in response to <jats:italic>Raldh2</jats:italic> but can be maintained during optic cup formation by a gene other than <jats:italic>Raldh1</jats:italic>, most likely <jats:italic>Raldh3</jats:italic>. Loss of optic vesicle RA signaling does not effect expression of early determinants of retina at the optic vesicle stage (<jats:italic>Pax6</jats:italic>, <jats:italic>Six3</jats:italic>, <jats:italic>Rx</jats:italic>, <jats:italic>Mitf</jats:italic>). Our findings suggest that RA functions as one of the signals needed for invagination of the retina to generate an optic cup. Developmental Dynamics 231:270–277, 2004. © 2004 Wiley‐Liss, Inc.</jats:p>","journal":"Developmental Dynamics","year":2004,"id":614900,"datarank":0.6814942173405006,"base_score":4.543294782270004,"endowment":4.543294782270004,"self_citation_contribution":0.6814942173405006,"citation_network_contribution":0.0,"self_endowment_contribution":0.6814942173405006,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":93,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":540501,"name":"Andrei Molotkov","orcid":null,"position":1,"is_corresponding":false},{"id":720110,"name":"Natalia Molotkova","orcid":null,"position":2,"is_corresponding":false},{"id":45536,"name":"Gregg Duester","orcid":"0000-0003-4335-3650","position":3,"is_corresponding":false},{"id":1584645,"name":"Felix A. 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Here, we demonstrate that <jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> embryos lacking RA synthesis in the optic vesicle exhibit a failure in retina invagination needed to develop an optic cup. This was also observed in <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup>:<jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> double mutants, which develop similarly. Both mutants retain RA activity in the lens placode associated with <jats:italic>Raldh3</jats:italic> expression, but this RA activity is insufficient to induce optic cup formation. Maternal RA administration at the optic vesicle stage rescues optic cup formation in <jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> and <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup>:<jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> embryos, demonstrating that <jats:italic>Raldh1</jats:italic> is not required during rescue of optic cup development. The optic cup of rescued <jats:italic>Raldh1</jats:italic><jats:sup>‐/‐</jats:sup>:<jats:italic>Raldh2</jats:italic><jats:sup>‐/‐</jats:sup> embryos exhibits normal RA activity and this is associated with <jats:italic>Raldh3</jats:italic> expression in the retina and lens. Thus, RA signaling initiates in the optic vesicle in response to <jats:italic>Raldh2</jats:italic> but can be maintained during optic cup formation by a gene other than <jats:italic>Raldh1</jats:italic>, most likely <jats:italic>Raldh3</jats:italic>. Loss of optic vesicle RA signaling does not effect expression of early determinants of retina at the optic vesicle stage (<jats:italic>Pax6</jats:italic>, <jats:italic>Six3</jats:italic>, <jats:italic>Rx</jats:italic>, <jats:italic>Mitf</jats:italic>). Our findings suggest that RA functions as one of the signals needed for invagination of the retina to generate an optic cup. 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