title: The Ptch1(DL) mouse: a new model to study lambdoid craniosynostosis and basal cell nevus syndrome-associated skeletal defects.
abstract: Mouse models provide valuable opportunities for probing the underlying pathology of human birth defects. By using an N-ethyl-N-nitrosourea-based screen for recessive mutations affecting craniofacial anatomy, we isolated a mouse strain, Dogface-like (DL), with abnormal skull and snout morphology. Examination of the skull indicated that these mice developed craniosynostosis of the lambdoid suture. Further analysis revealed skeletal defects related to the pathology of basal cell nevus syndrome (BCNS) including defects in development of the limbs, scapula, ribcage, secondary palate, cranial base, and cranial vault. In humans, BCNS is often associated with mutations in the Hedgehog receptor PTCH1 and genetic mapping in DL identified a point mutation at a splice donor site in Ptch1. By using genetic complementation analysis we determined that DL is a hypomorphic allele of Ptch1, leading to increased Hedgehog signaling. Two aberrant transcripts are generated by the mutated Ptch1(DL) gene, which would be predicted to reduce significantly the levels of functional Patched1 protein. This new Ptch1 allele broadens the mouse genetic reagents available to study the Hedgehog pathway and provides a valuable means to study the underlying skeletal abnormalities in BCNS. In addition, these results strengthen the connection between elevated Hedgehog signaling and craniosynostosis.
authors.affiliation: Department of Craniofacial Biology and Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Feng
authors.forename: Irene
authors.initials: I
authors.lastname: Choi
authors.forename: David E
authors.initials: DE
authors.lastname: Clouthier
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
authors.forename: Trevor
authors.initials: T
authors.lastname: Williams
mesh_terms: D000818:Animals; D001478:Basal Cell Nevus Syndrome / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D001842:Bone and Bones / Q000002:abnormalities* / Q000196:embryology; D003398:Craniosynostoses / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D012886:Skull / Q000002:abnormalities / Q000196:embryology
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface
keywords: Hedgehog; craniofacial defects; craniosynostosis; omphalocele; polydactyly
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