{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T18:27:08Z","timestamp":1792261628154,"version":"4.4.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T00:00:00Z","timestamp":1586390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30 EY007003"],"award-info":[{"award-number":["P30 EY007003"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Society"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL125774"],"award-info":[{"award-number":["R01 HL125774"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL124232"],"award-info":[{"award-number":["R01 HL124232"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 30428"],"award-info":[{"award-number":["R01 30428"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Combined pituitary hormone deficiency (CPHD) is a genetically heterogeneous disorder caused by mutations in over 30 genes. The loss-of-function mutations in many of these genes, including orthodenticle homeobox 2 (OTX2), can present with a broad range of clinical symptoms, which provides a challenge for predicting phenotype from genotype. Another challenge in human genetics is functional evaluation of rare genetic variants that are predicted to be deleterious. Zebrafish are an excellent vertebrate model for evaluating gene function and disease pathogenesis, especially because large numbers of progeny can be obtained, overcoming the challenge of individual variation. To clarify the utility of zebrafish for the analysis of CPHD-related genes, we analyzed the effect of OTX2 loss of function in zebrafish. The otx2b gene is expressed in the developing hypothalamus, and otx2bhu3625\/hu3625 fish exhibit multiple defects in the development of head structures and are not viable past 10\u00a0days post fertilization (dpf). Otx2bhu3625\/hu3625 fish have a small hypothalamus and low expression of pituitary growth hormone and prolactin (prl). The gills of otx2bhu3625\/hu3625 fish have weak sodium influx, consistent with the role of prolactin in osmoregulation. The otx2bhu3625\/hu3625 eyes are microphthalmic with colobomas, which may underlie the inability of the mutant fish to find food. The small pituitary and eyes are associated with reduced cell proliferation and increased apoptosis evident at 3 and 5 dpf, respectively. These observations establish the zebrafish as a useful tool for the analysis of CPHD genes with variable and complex phenotypes.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa064","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T19:10:14Z","timestamp":1585854614000},"page":"1648-1657","source":"Crossref","is-referenced-by-count":10,"title":["Otx2b mutant zebrafish have pituitary, eye and mandible defects that model mammalian disease"],"prefix":"10.1093","volume":"29","author":[{"given":"Hironori","family":"Bando","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gergics","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda L","family":"Bohnsack","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P","family":"Toolan","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E","family":"Richter","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan A","family":"Shavit","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally A","family":"Camper","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,9]]},"reference":[{"key":"2020062904235777900_ref1","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/358687a0","article-title":"Nested expression domains of four homeobox genes in developing rostral brain","volume":"358","author":"Simeone","year":"1992","journal-title":"Nature"},{"key":"2020062904235777900_ref2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1136\/jmedgenet-2012-100892","article-title":"OTX2 mutations contribute to the otocephaly-dysgnathia complex","volume":"49","author":"Chassaing","year":"2012","journal-title":"J. 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