Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations.
The 22q11 deletion (22q11DS; velo-cardio-facial syndrome/DiGeorge syndrome) is characterized by defects in the derivatives of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1, a member of the T-box family of transcription factors, as being responsible for the physical malformations of the syndrome. Mice heterozygous for a null mutation in Tbx1 have mild anomalies, whereas homozygous Tbx1 mutants die at birth with severe defects in the derivatives of the pharyngeal apparatus, including cleft palate, thymus gland aplasia and cardiac outflow tract malformations. Tbx1 is expressed in the splanchnic mesenchyme, the pharyngeal endoderm (PE) and in the core mesoderm of the pharyngeal apparatus. Tissue interactions between the epithelia and mesenchyme of the arches are required for development of the pharyngeal apparatus; the precise role of Tbx1 in each tissue is not known. To assess the role of Tbx1 in the PE, a conditional allele of Tbx1 was generated using the Cre/loxP system. Foxg1-Cre was used to drive PE-specific ablation of Tbx1. Conditional null mutants survived embryogenesis, but died in the neonatal period with malformations identical to the defects observed in Tbx1 homozygous null mutants. The abnormalities appear to be secondary to failed outgrowth of the pharyngeal pouches. These results show that Tbx1 in the PE is required for the patterning and development of the pharyngeal apparatus, thereby disrupting the formation of its derivative structures.
Arnold
Jelena S
JS
Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Werling
Uwe
U
Braunstein
Evan M
EM
Liao
Jun
J
Nowotschin
Sonja
S
Edelmann
Winfried
W
Hebert
Jean M
JM
Morrow
Bernice E
BE
D000818:Animals; D018376:Cardiovascular Abnormalities / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D004707:Endoderm / Q000378:metabolism*; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000196:embryology; D009154:Mutation; D010280:Parathyroid Glands / Q000196:embryology; D010614:Pharynx / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D013950:Thymus Gland / Q000196:embryology
C496456:FGF8 protein, human; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051524:Fibroblast Growth Factor 8