{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:44:44Z","timestamp":1778625884829,"version":"3.51.4"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["17K19738"],"award-info":[{"award-number":["17K19738"]}]},{"name":"JSPS KAKENHI","award":["17ek0109217h0001"],"award-info":[{"award-number":["17ek0109217h0001"]}]},{"name":"JSPS KAKENHI","award":["28-2"],"award-info":[{"award-number":["28-2"]}]},{"name":"AMED","award":["17K19738"],"award-info":[{"award-number":["17K19738"]}]},{"name":"AMED","award":["17ek0109217h0001"],"award-info":[{"award-number":["17ek0109217h0001"]}]},{"name":"AMED","award":["28-2"],"award-info":[{"award-number":["28-2"]}]},{"name":"National Center for Child Health and Development","award":["17K19738"],"award-info":[{"award-number":["17K19738"]}]},{"name":"National Center for Child Health and Development","award":["17ek0109217h0001"],"award-info":[{"award-number":["17ek0109217h0001"]}]},{"name":"National Center for Child Health and Development","award":["28-2"],"award-info":[{"award-number":["28-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The eye primordium of vertebrates initially forms exactly at the side of the head. Later, the eyeball architecture is tuned to see ahead with better visual acuity, but its molecular basis is unknown. The position of both eyes in the face alters in patients with holoprosencephaly due to Sonic hedgehog (Shh) mutations that disturb the development of the ventral midline of the neural tube. However, patient phenotypes vary extensively, and microforms without a brain anomaly relate instead to alternation of gene expression of the Shh signaling center in the facial primordia. We identified novel missense mutations of the Shh gene in two patients with a dislocated fovea, where the photoreceptor cells are condensed. Functional assays showed that Shh upregulates Patched and Gli and downregulates Pax6, and that Shh mutations alter these activities. Gain of function of Shh in a chick embryo retards retinal development and eyeball growth depending on the location of Shh expression, while loss of function of Shh promotes these features. We postulate that a signaling molecule like Shh that emanates from the face controls the extent of differentiation of the neural retina in a position-specific manner and that this may result in the formation of the fovea at the correct location.<\/jats:p>","DOI":"10.3390\/ijms26020496","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T07:00:47Z","timestamp":1736406047000},"page":"496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sonic Hedgehog Determines Early Retinal Development and Adjusts Eyeball Architecture"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0332-8100","authenticated-orcid":false,"given":"Noriyuki","family":"Azuma","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Laboratory for Visual Science, National Centre for Child Health and Development, Tokyo 157-8535, Japan"},{"name":"Department of Developmental and Regenerative Biology, Medical Research Institute, Institute of Science Tokyo, Tokyo 113-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Tadokoro","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Nakafuku","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan"},{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Research Foundation, Cincinnati, OH 45229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Nishina","sequence":"additional","affiliation":[{"name":"Department of Developmental and Regenerative Biology, Medical Research Institute, Institute of Science Tokyo, Tokyo 113-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"ref_1","unstructured":"Rodieck, R.W. 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