{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:48:11Z","timestamp":1790246891391,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,1,24]],"date-time":"2012-01-24T00:00:00Z","timestamp":1327363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Developmental Dynamics"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:styled-content>Background<\/jats:styled-content>: The Frontonasal Ectodermal Zone (FEZ) is a signaling center in the face that expresses <jats:italic>Sonic hedgehog<\/jats:italic> (<jats:italic>Shh<\/jats:italic>) and regulates patterned growth of the upper jaw. Blocking SHH in the forebrain blocks <jats:italic>Shh<\/jats:italic> expression in the FEZ and creates malformations resembling holoprosencephaly (HPE), while inhibition of BMP signaling in the mesenchyme blocks FEZ formation and causes similar dysmorphology. Thus, the brain could regulate FEZ formation by SHH or BMP signaling, and if so, activating one of these pathways in the face might alleviate the effects of repression of SHH in the brain. <jats:styled-content>Results<\/jats:styled-content>: We blocked SHH signaling in the brain while adding SHH or BMP between the neural and facial ectoderm of the frontonasal process. When applied early, SHH restored <jats:italic>Shh<\/jats:italic> expression in the FEZ and significantly improved shape outcomes, which contrasts with our previous experiments that showed later SHH treatments have no effect. BMP\u2010soaked beads introduced early and late caused apoptosis that exacerbated malformations. Finally, removal of <jats:italic>Smoothened<\/jats:italic> from neural crest cells did not inhibit <jats:italic>Shh<\/jats:italic> expression in the FEZ. <jats:styled-content>Conclusions<\/jats:styled-content>: Collectively, this work suggests that a direct, time\u2010sensitive SHH signal from the brain is required for the later induction of <jats:italic>Shh<\/jats:italic> in the FEZ. We propose a testable model of FEZ activation and discuss signaling mediators that may regulate these interactions. Developmental Dynamics 241:247\u2013256, 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/dvdy.23726","type":"journal-article","created":{"date-parts":[[2011,12,19]],"date-time":"2011-12-19T10:38:33Z","timestamp":1324291113000},"page":"247-256","source":"Crossref","is-referenced-by-count":47,"title":["Signaling by SHH rescues facial defects following blockade in the brain"],"prefix":"10.1002","volume":"241","author":[{"given":"H. 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