Manipulation of endogenous regulatory elements and transgenic analyses of the Tbx1 gene.
Pharyngeal morphogenesis is a complex process involving precise coordination of multiple cell types and transcription networks. TBX1 heterozygous mutation causes DiGeorge Syndrome, a typical disorder of pharyngeal development. In mice, loss of function of Tbx1 causes severe disruption of pharyngeal development. Therefore, to understand the regulatory circuits controlling the pharyngeal apparatus, it is important to understand how Tbx1 is regulated. Transgenic experiments had shown that a Forkhead (Fox) transcription factor binding site is required for the activity of a Tbx1 enhancer driving expression in many of the endogenous domains. In this study we carried out manipulation of regulatory elements of the endogenous gene in mice and extensive transgenic analysis of the Tbx1 locus. Results indicated that the Fox binding site is dispensable for Tbx1 gene expression, but the enhancer within which it is located regulates, to a limited extent, mesodermal expression of the gene. Transgenic analysis of conserved noncoding regions within 54 kb of the Tbx1 locus identified a novel pharyngeal endoderm-specific enhancer and an intronic suppressor element. Overall, our data suggest a regulatory architecture of the Tbx1 gene made of tissue-specific modules and redundant elements that individually contribute, to a modest extent, to the expression of the gene.
Institute of Biosciences and Technologies, Texas A&M University, Houston, TX 77843, USA.
Zhen
Z
Zhang
Antonio
A
Baldini
D000818:Animals; D001934:Branchial Region / Q000378:metabolism; D003433:Crosses, Genetic; D004707:Endoderm / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000235:genetics*; D019076:Transgenes
D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse