Deletion of the T-box transcription factor gene, Tbx1, in mice induces differential expression of genes associated with cleft palate in humans.

OBJECTIVE: We examined the function of the T-box transcription factor 1 (TBX1) in palatogenesis.

DESIGN: Tbx1-knockout mice were histologically examined by hematoxylin and eosin staining. Next, secondary palatal shelves dissected from wild type or Tbx1-knockout mice embryos at embryonic day 13.5 were investigated with microarray analysis, gene ontology analysis, and real-time quantitative polymerase chain reaction. We performed gene profiling of developing palatal shelves from wild type and Tbx1-knockout embryos. We also analyzed the association of mouse genes linked to cleft palate with biological processes and compared the results with those of our ontology analysis of dysregulated genes in Tbx1-knockout palatal shelves.

RESULTS: Histological analysis of Tbx1-knockout palate with complete cleft palate at postnatal day 1 showed aplasia of secondary palates associated with a small mandible and a small tongue compared to wild type littermates. Gene ontology analysis indicated that genes associated with development of the nervous system, muscle, and biomineral tissue were dysregulated in Tbx1-knockout palatal shelves. Furthermore, in Tbx1-knockout palatal shelves, genes associated with human cleft palate, specifically, myosin heavy chain 3 (Myh3) and nebulin (Neb), were downregulated and gamma-aminobutyric acid type A receptor beta 3 subunit (Gabrb3) was upregulated.

CONCLUSIONS: Our findings demonstrate that TBX1 maintains normal growth and development of palatal shelves, mediated through the regulation of genes involved in muscle cell differentiation, nervous system development, and biomineral tissue development. Multiple factors in Tbx1-knockout mice may lead to various subtypes of cleft palate.