{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:46:00Z","timestamp":1790711160042,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2010,3,8]],"date-time":"2010-03-08T00:00:00Z","timestamp":1268006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2010,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The Hedgehog (Hh) pathway provides inductive signals critical for developmental patterning of the brain and face. In humans and in animal models interference with this pathway yields birth defects, among the most well\u2010studied of which fall within the holoprosencephaly (HPE) spectrum.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Timed\u2010pregnant C57Bl\/6J mice were treated with the natural Hh signaling antagonist cyclopamine by subcutaneous infusion from gestational day (GD) 8.25 to 9.5, or with a potent cyclopamine analog, AZ75, administered by oral gavage at GD 8.5. Subsequent embryonic morphogenesis and fetal central nervous system (CNS) phenotype were respectively investigated by scanning electron microscopy and high resolution magnetic resonance imaging (MRI).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In utero Hh signaling antagonist exposure induced a spectrum of craniofacial and brain malformations. Cyclopamine exposure caused lateral cleft lip and palate (CLP) defects attributable to embryonic deficiency of midline and lower medial nasal prominence tissue. The CLP phenotype was accompanied by olfactory bulb hypoplasia and anterior pituitary aplasia, but otherwise grossly normal brain morphology. AZ75 exposure caused alobar and semilobar HPE with associated median facial deficiencies. An intermediate phenotype of median CLP was produced infrequently by both drug administration regimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The results of this study suggest that interference with Hh signaling should be considered in the CLP differential and highlight the occurrence of CNS defects that are expected to be present in a cohort of patients having CLP. This work also illustrates the utility of fetal MRI\u2010based analyses and establishes a novel mouse model for teratogen\u2010induced CLP. Birth Defects Research (Part A), 2010. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.20656","type":"journal-article","created":{"date-parts":[[2010,3,8]],"date-time":"2010-03-08T14:24:47Z","timestamp":1268058287000},"page":"232-240","source":"Crossref","is-referenced-by-count":74,"title":["Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications"],"prefix":"10.1002","volume":"88","author":[{"given":"Robert J.","family":"Lipinski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihwa","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen K.","family":"Sulik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L.","family":"Everson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry J.","family":"Gipp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wade","family":"Bushman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J.","family":"Rowland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,4,6]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"36","article-title":"Image processing with ImageJ","volume":"11","author":"Abramoff MD","year":"2004","journal-title":"Biophotonics International"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.162356199"},{"key":"e_1_2_6_4_1","first-page":"106","article-title":"Mouse Shh is required for prechordal plate maintenance during brain and craniofacial morphogenesis","volume":"327","author":"Aoto K","year":"2009","journal-title":"Dev Dio"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.17796\/jcpd.33.3.c244761467507721"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040232"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1025302"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20295"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.2466\/pms.106.1.197-206"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200419596"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100249900004"},{"key":"e_1_2_6_12_1","first-page":"247","article-title":"A comparative study of craniofacial growth during secondary palate development in four strains of mice","volume":"2","author":"Diewert VM","year":"1982","journal-title":"J Craniofac Genet Dev Biol"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/10454411920040010201"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-8"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000066748"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.2632"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/OGX.0b013e3181641278"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-4924-1-10"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20193"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(08)00602-9"},{"key":"e_1_2_6_21_1","first-page":"471","article-title":"Maxillary arch dimensions in normal and unilateral cleft palate subjects","volume":"6","author":"Huddart AG","year":"1969","journal-title":"Cleft Palate J"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00000653"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.938601"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1190304"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20646"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20430"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02533750"},{"key":"e_1_2_6_28_1","first-page":"576","article-title":"Pituitary growth hormone insufficiency associated with cleft lip and palate. 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