Tbx1is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer

Abstract

Haploinsufficiency of Tbx1 is likely a major determinant of cardiac and craniofacial birth defects associated with DiGeorge syndrome. Although mice deficient in Tbx1 exhibit pharyngeal and aortic arch defects, the developmental program and mechanisms through which Tbx1 functions are relatively unknown. We identified a singlecis-element upstream ofTbx1that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation ofTbx1transcription in the pharyngeal endoderm and head mesenchyme. TheTbx1regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. We show that Shh is necessary for aortic arch development, similar to Tbx1, and is also required for expression ofFoxa2andFoxc2in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the criticalcis-element upstream ofTbx1, and Foxc proteins were required, within their expression domains, forTbx1transcription in vivo. We propose thatTbx1is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation ofTbx1.