{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T07:45:31Z","timestamp":1767339931376,"version":"3.41.2"},"reference-count":65,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":1964,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS039421"],"award-info":[{"award-number":["R01 NS039421"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R01 AA018825"],"award-info":[{"award-number":["R01 AA018825"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Septo-optic dysplasia (SOD) is a congenital disorder characterized by optic nerve, pituitary and midline brain malformations. The clinical presentation of SOD is highly variable with a poorly understood etiology. The majority of SOD cases are sporadic, but in rare instances inherited mutations have been identified in a small number of transcription factors, some of which regulate the expression of Sonic hedgehog (Shh) during mouse forebrain development. SOD is also associated with young maternal age suggesting that environmental factors, including alcohol consumption at early stages of pregnancy, may increase the risk of developing this condition. Here, we address the hypothesis that SOD is a multifactorial disorder stemming from interactions between mutations in Shh pathway genes and prenatal ethanol exposure. Mouse embryos with mutations in the Shh co-receptor, Cdon, were treated in utero with ethanol or saline at embryonic day 8 (E8.0) and evaluated for optic nerve hypoplasia (ONH), a prominent feature of SOD. We show that both Cdon\u2212\/- mutation and prenatal ethanol exposure independently cause ONH through a similar pathogenic mechanism that involves selective inhibition of Shh signaling in retinal progenitor cells, resulting in their premature cell-cycle arrest, precocious differentiation and failure to properly extend axons to the optic nerve. The ONH phenotype was not exacerbated in Cdon\u2212\/- embryos treated with ethanol suggesting that an intact Shh signaling pathway is required for ethanol to exert its teratogenic effects. These results support a model whereby mutations in Cdon and prenatal ethanol exposure increase SOD risk through spatiotemporal perturbations in Shh signaling activity.<\/jats:p>","DOI":"10.1242\/dmm.026195","type":"journal-article","created":{"date-parts":[[2016,11,25]],"date-time":"2016-11-25T01:35:19Z","timestamp":1480037719000},"source":"Crossref","is-referenced-by-count":19,"title":["Prenatal ethanol exposure phenocopies <i>Cdon<\/i> mutation by impeding Shh function in the etiology of optic nerve hypoplasia"],"prefix":"10.1242","author":[{"given":"Benjamin M.","family":"Kahn","sequence":"first","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya S.","family":"Corman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Korah","family":"Lovelace","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingi","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Krauss","sequence":"additional","affiliation":[{"name":"Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4274-4521","authenticated-orcid":false,"given":"Douglas J.","family":"Epstein","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2016,1,1]]},"reference":[{"key":"2021042701330014700_DMM026195C1","doi-asserted-by":"publisher","first-page":"10476","DOI":"10.1073\/pnas.162356199","article-title":"Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure","volume":"99","author":"Ahlgren","year":"2002","journal-title":"Proc. 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