Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer

Hiroyuki Yamagishi; Jun Maeda; Tonghuan Hu; John McAnally; Simon J Conway; Tsutomu Kume; Erik N Meyers; Chihiro Yamagishi; Deepak Srivastava

doi:10.1101/gad.1048903

Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer

Genes Dev. 2003 Jan 15;17(2):269-81. doi: 10.1101/gad.1048903.

Authors

Hiroyuki Yamagishi¹, Jun Maeda, Tonghuan Hu, John McAnally, Simon J Conway, Tsutomu Kume, Erik N Meyers, Chihiro Yamagishi, Deepak Srivastava

Affiliation

¹ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA. Hiroyuki.Yamagishi@UTSouthwestern.edu

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 single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation of Tbx1 transcription in the pharyngeal endoderm and head mesenchyme. The Tbx1 regulatory 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 of Foxa2 and Foxc2 in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the critical cis-element upstream of Tbx1, and Foxc proteins were required, within their expression domains, for Tbx1 transcription in vivo. We propose that Tbx1 is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation of Tbx1.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology
DiGeorge Syndrome / embryology
DiGeorge Syndrome / genetics
Disease Models, Animal
Enhancer Elements, Genetic
Forkhead Transcription Factors
Gene Expression Regulation, Developmental
Hedgehog Proteins
Hepatocyte Nuclear Factor 3-beta
Humans
Mice
Mice, Knockout
Mice, Mutant Strains
Mice, Transgenic
Models, Biological
Nuclear Proteins / genetics
Nuclear Proteins / physiology*
Organ Specificity
Signal Transduction
T-Box Domain Proteins / deficiency
T-Box Domain Proteins / genetics*
T-Box Domain Proteins / physiology*
Trans-Activators / genetics*
Transcription Factors / genetics
Transcription Factors / physiology*

Substances

DNA-Binding Proteins
FOXA2 protein, human
FOXC1 protein, human
Forkhead Transcription Factors
Foxa2 protein, mouse
Foxc1 protein, mouse
Hedgehog Proteins
Nuclear Proteins
SHH protein, human
Shh protein, mouse
T-Box Domain Proteins
TBX1 protein, human
Tbx1 protein, mouse
Trans-Activators
Transcription Factors
mesenchyme fork head 1 protein
Hepatocyte Nuclear Factor 3-beta