Role of Tbx1, the 22q11 deletion syndrome candidate gene, in mouse development

Abstract

Velo-cardio-facial syndrome/DiGeorge/22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, occurring in 1/4000 live births. The syndrome is characterized by defects in the derivatives of the pharyngeal apparatus (PA), including craniofacial anomalies, thymus gland hypoplasia or aplasia and cardiovascular defects. Mouse genetic studies have identified Tbx1, a member of the T-box family of transcription factors, as a key gene in the etiology of the syndrome. Mice heterozygous for a null mutation in Tbx1 develop mild cardiovascular defects while homozygous Tbx1-/- embryos die at birth with severe congenital defects stemming from abnormal PA development. Throughout embryogenesis Tbx1 is expressed in multiple interacting tissues, including the endoderm and the non-neural crest core mesoderm of the PA as well as the otic vesicle epithelium and the adjacent periotic mesenchyme. To assess the role of Tbx1 in each interacting tissue during embryonic development, I have conditionally inactivated the gene in the pharyngeal endoderm and in the otic vesicle using the Cre/LoxP system. Tissue specific ablation of Tbx1 in the Foxg1 domain causes a severe pharyngeal phenotype, including neonatal lethality, craniofacial defects with cleft palate, absence of middle and outer ear structures, and thymus and parathyroid gland aplasia. Inactivation of Tbx1 in the otic vesicle using the Foxg1-Cre and Pax2-Cre strains results in both hypoplasia of the inner ear sensory structures and duplication of the cochleovestibular ganglion. Overall, Tbx1 conditional mutants do not differ significantly from the previously described homozygous null mutants, underlying the importance of endodermal and otic vesicle driven Tbx1 expression. These results suggest that signaling from these structures is critical for proper development of the embryo. Finally, my data contribute significantly to the understanding of congenital defects observed in 22q11DS patients as they help elucidate the mechanisms responsible for pharyngeal endoderm outgrowth and its patterning into distinct structures.