title: Noggin null allele mice exhibit a microform of holoprosencephaly.
abstract: Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin(-/-) mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin(-/-) mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin(-/-) mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HPE.
authors.affiliation: Department of Craniofacial Development, King's College, London, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Lana-Elola
authors.forename: Przemko
authors.initials: P
authors.lastname: Tylzanowski
authors.forename: Maarit
authors.initials: M
authors.lastname: Takatalo
authors.forename: Kirsi
authors.initials: K
authors.lastname: Alakurtti
authors.forename: Lotta
authors.initials: L
authors.lastname: Veistinen
authors.forename: Thimios A
authors.initials: TA
authors.lastname: Mitsiadis
authors.forename: Daniel
authors.initials: D
authors.lastname: Graf
authors.forename: Ritva
authors.initials: R
authors.lastname: Rice
authors.forename: Frank P
authors.initials: FP
authors.lastname: Luyten
authors.forename: David P
authors.initials: DP
authors.lastname: Rice
mesh_terms: D000483:Alleles; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005145:Face / Q000196:embryology; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D016142:Holoprosencephaly / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009055:Mouth / Q000196:embryology / Q000378:metabolism; D010159:Palate / Q000196:embryology / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D010902:Pituitary Gland / Q000002:abnormalities; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D019147:Vomeronasal Organ / Q000002:abnormalities; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D051524:Fibroblast Growth Factor 8; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D000099176:Noggin Protein; C496457:Fgf8 protein, mouse; C000606236:PTCH1 protein, human; C000606240:Ptch1 protein, mouse