Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect.
Congenital bony syngnathia, a rare but severe human birth defect, is characterized by bony fusion of the mandible to the maxilla. However, the genetic mechanisms underlying this birth defect are poorly understood, largely due to limitation of available animal models. Here we present evidence that transgenic expression of Bmp4 in neural crest cells causes a series of craniofacial malformations in mice, including a bony fusion between the maxilla and hypoplastic mandible, resembling the bony syngnathia syndrome in humans. In addition, the anterior portion of the palatal shelves emerged from the mandibular arch instead of the maxilla in the mutants. Gene expression assays showed an altered expression of several facial patterning genes, including Hand2, Dlx2, Msx1, Barx1, Foxc2 and Fgf8, in the maxillary and mandibular processes of the mutants, indicating mis-patterned cranial neural crest (CNC) derived cells in the facial region. However, despite of formation of cleft palate and ectopic cartilage, forced expression of a constitutively active form of BMP receptor-Ia (caBmprIa) in CNC lineage did not produce the syngnathia phenotype, suggesting a non-cell autonomous effect of the augmented BMP4 signaling. Our studies demonstrate that aberrant BMP4-mediated signaling in CNC cells leads to mis-patterned facial skeleton and congenital bony syngnathia, and suggest an implication of mutations in BMP signaling pathway in human bony syngnathia.
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Fenglei
F
He
South China Center for Biomedical Research, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, PR China.
Xuefeng
X
Hu
Department of Cellular and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
Wei
W
Xiong
Department of Cellular and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
Lu
L
Li
Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China.
Lisong
L
Lin
South China Center for Biomedical Research, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, PR China.
Bin
B
Shen
Department of Cellular and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, Guangdong Province, PR China.
Ling
L
Yang
Department of Cellular and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
Shuping
S
Gu
South China Center for Biomedical Research, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, PR China.
Yanding
Y
Zhang
South China Center for Biomedical Research, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, PR China; Department of Cellular and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. Electronic address: ychen@tulane.edu.
YiPing
Y
Chen
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics; D005147:Facial Bones / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development; D006801:Humans; D007569:Jaw Abnormalities / Q000235:genetics*; D008334:Mandible / Q000002:abnormalities* / Q000196:embryology; D008437:Maxilla / Q000002:abnormalities* / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051155:Wnt1 Protein / Q000235:genetics
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
Bmp signaling; Cleft palate; Cranial neural crest; Craniofacial patterning; Syngnathia