Tbx1 and Brn4 regulate retinoic acid metabolic genes during cochlear morphogenesis.

Background: In vertebrates, the inner ear is comprised of the cochlea and vestibular system, which develop from the otic vesicle. This process is regulated via inductive interactions from surrounding tissues. Tbx1, the gene responsible for velo-cardio-facial syndrome/DiGeorge syndrome in humans, is required for ear development in mice.

T-genes and limb bud development.

The T-box family of transcriptional factors is ancient and highly conserved among most species of animals. Haploinsufficiency of multiple T-box proteins results in severe human congenital malformation syndromes, involving craniofacial, cardiovascular, and skeletal structures. These genes have major roles in embryogenesis, including the development of the limbs.

Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.

Most 22q11.2 deletion syndrome (22q11DS) patients have middle and outer ear anomalies, whereas some have inner ear malformations. Tbx1, a gene hemizygously deleted in 22q11DS patients and required for ear development, is expressed in multiple tissues during embryogenesis.

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.

Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de novo hemizygous 22q11.2 deletions and is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The main physical findings include aortic arch and outflow tract heart defects, thymus gland hypoplasia or aplasia and craniofacial anomalies.