Document Detail


Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients.
MedLine Citation:
PMID:  22156581     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ryan Humphreys; Wei Zheng; Lawrence S Prince; Xianghu Qu; Christopher Brown; Kathleen Loomes; Stacey S Huppert; Scott Baldwin; Steven Goudy
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-08
Journal Detail:
Title:  Human molecular genetics     Volume:  21     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-23     Completed Date:  2012-08-07     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1374-83     Citation Subset:  IM    
Affiliation:
Department of Surgery, Vanderbilt Medical Center, Nashville, TN 37232, USA.
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MeSH Terms
Descriptor/Qualifier:
Alagille Syndrome / physiopathology*
Animals
Blotting, Western
Calcium-Binding Proteins / physiology*
Cells, Cultured
Craniofacial Abnormalities / etiology*,  metabolism,  pathology
Embryo, Mammalian / cytology,  metabolism
Female
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Integrases / metabolism
Intercellular Signaling Peptides and Proteins / physiology*
Membrane Proteins / physiology*
Mesoderm / metabolism,  pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Morphogenesis
Neural Crest / cytology,  metabolism*
Phenotype
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptor, Notch1 / physiology*
Reverse Transcriptase Polymerase Chain Reaction
Wnt1 Protein / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
DK078640/DK/NIDDK NIH HHS; HL086324/HL/NHLBI NIH HHS; HL086964/HL/NHLBI NIH HHS; HL092551/HL/NHLBI NIH HHS; HL097195/HL/NHLBI NIH HHS; HL105334/HL/NHLBI NIH HHS; K08 DE017953/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Intercellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Notch1 protein, mouse; 0/RNA, Messenger; 0/Receptor, Notch1; 0/Wnt1 Protein; 0/Wnt1 protein, mouse; 134324-36-0/Serrate proteins; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases
Comments/Corrections
Erratum In:
Hum Mol Genet. 2012 Jun 15;21(12):2843

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