Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients.

Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE

Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-

Alagille Syndrome/*physiopathology ; Calcium-Binding Proteins/*physiology ; Craniofacial Abnormalities/*etiology ; Intercellular Signaling Peptides and Proteins/*physiology ; Membrane Proteins/*physiology ; Neural Crest/*metabolism ; Receptor, Notch1/*physiology; Animals ; Blotting, Western ; Cells, Cultured ; Craniofacial Abnormalities/metabolism ; Craniofacial Abnormalities/pathology ; Embryo, Mammalian/cytology ; Embryo, Mammalian/metabolism ; Female ; Fluorescent Antibody Technique ; Humans ; Immunoenzyme Techniques ; Integrases/metabolism ; Jagged-1 Protein ; Mesoderm/metabolism ; Mesoderm/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Morphogenesis ; Neural Crest/cytology ; Phenotype ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Serrate-Jagged Proteins ; Wnt1 Protein/genetics ; Wnt1 Protein/metabolism

JAGGED1 mutations cause Alagille syndrome, comprising a constellation of clinical findings, including biliary, cardiac and craniofacial anomalies. Jagged1, a ligand in the Notch signaling pathway, has been extensively studied during biliary and cardiac development. However, the role of JAGGED1 during craniofacial development is poorly understood. Patients with Alagille syndrome have midface hypoplasia giving them a characteristic 'inverted V' facial appearance. This study design determines the requirement of Jagged1 in the cranial neural crest (CNC) cells, which encompass the majority of mesenchyme present during craniofacial development. Furthermore, with this approach, we identify the autonomous and non-autonomous requirement of Jagged1 in a cell lineage-specific approach during midface development. Deleting Jagged1 in the CNC using Wnt1-cre; Jag1 Flox/Flox recapitulated the midfacial hypoplasia phenotype of Alagille syndrome. The Wnt1-cre; Jag1 Flox/Flox mice die at postnatal day 30 due to inability to masticate owing to jaw misalignment and poor occlusion. The etiology of midfacial hypoplasia in the Wnt1-cre; Jag1 Flox/Flox mice was a consequence of reduced cellular proliferation in the midface, aberrant vasculogenesis with decreased productive vessel branching and reduced extracellular matrix by hyaluronic acid staining, all of which are associated with midface anomalies and aberrant craniofacial growth. Deletion of Notch1 from the CNC using Wnt1-cre; Notch1 F/F mice did not recapitulate the midface hypoplasia of Alagille syndrome. These data demonstrate the requirement of Jagged1, but not Notch1, within the midfacial CNC population during development. Future studies will investigate the mechanism in which Jagged1 acts in a cell autonomous and cell non-autonomous manner.

Erratum in: Hum Mol Genet. 2012 Jun 15;21(12):2843.

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HL092551 United States HL NHLBI NIH HHS; DK078640 United States DK NIDDK NIH HHS; HL097195 United States HL NHLBI NIH HHS; R01 DK078640 United States DK NIDDK NIH HHS; R01 HL097195 United States HL NHLBI NIH HHS; HL086324 United States HL NHLBI NIH HHS; K08 DE017953 United States DE NIDCR NIH HHS; HL086964 United States HL NHLBI NIH HHS; R01 HL086324 United States HL NHLBI NIH HHS; HL105334 United States HL NHLBI NIH HHS

0 (Calcium-Binding Proteins)
0 (Intercellular Signaling Peptides and Proteins)
0 (JAG1 protein, human)
0 (Jag1 protein, mouse)
0 (Jagged-1 Protein)
0 (Membrane Proteins)
0 (Notch1 protein, mouse)
0 (RNA, Messenger)
0 (Receptor, Notch1)
0 (Serrate-Jagged Proteins)
0 (Wnt1 Protein)
0 (Wnt1 protein, mouse)
EC 2.7.7.- (Cre recombinase)
EC 2.7.7.- (Integrases)

Date Created: 20111214 Date Completed: 20120807 Latest Revision: 20211021

20240829

PMC3465692

10.1093/hmg/ddr575

22156581