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Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer
Hiroyuki Yamagishi1, Jun Maeda, Tonghuan Hu
1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA. Hiroyuki.Yamagishi@UTSouthwestern.edu
Genes & Development
|January 21, 2003
Summary
Tbx1 gene defects cause DiGeorge syndrome birth defects. Sonic hedgehog signaling and Fox transcription factors regulate Tbx1, revealing a key mechanism in pharyngeal development.
Area of Science:
- Developmental biology
- Genetics
- Molecular biology
Background:
- Haploinsufficiency of Tbx1 is linked to DiGeorge syndrome, causing cardiac and craniofacial defects.
- The precise developmental role and regulatory mechanisms of Tbx1 remain largely uncharacterized.
Purpose of the Study:
- To elucidate the regulatory network controlling Tbx1 expression.
- To investigate the role of Sonic hedgehog (Shh) signaling and Fox transcription factors in Tbx1 regulation.
Main Methods:
- Identification and characterization of a cis-element regulating Tbx1 transcription.
- In vivo studies assessing the response to Shh signaling.
- Analysis of Fox protein binding and transcriptional activation.
Main Results:
- A critical cis-element upstream of Tbx1 was identified, essential for its transcription in pharyngeal endoderm and head mesenchyme.
- Shh signaling regulates Tbx1 expression and is crucial for aortic arch development.
- Foxa2, Foxc1, and Foxc2 transcription factors bind to the cis-element and activate Tbx1 transcription, with Foxc proteins being essential in vivo.
Conclusions:
- Tbx1 is a direct transcriptional target of Fox proteins.
- Fox proteins act as intermediaries in Shh-mediated regulation of Tbx1.
- This regulatory pathway is critical for normal pharyngeal and aortic arch development, offering insights into DiGeorge syndrome etiology.