Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field

Sonja Nowotschin, Jun Liao, Philip J. Gage, Jonathan A. Epstein, Marina Campione, Bernice E. Morrow

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Individuals with 22q11 deletion syndrome (22q11DS; DiGeorge/ velo-cardio-facial syndrome) have multiple congenital malformations, including cardiovascular defects. Most individuals with this syndrome possess 1.5-3.0 Mb hemizygous 22q11.2 deletions. The T-box transcription factor TBX1, lies within the nested 1.5 Mb interval and is a strong candidate for its etiology. Inactivation of Tbx1 in the mouse results in neonatal lethality owing to the presence of a single cardiac outflow tract. One important goal is to understand the molecular pathogenesis of cardiovascular defects in this syndrome. However, the molecular pathways of Tbx1 are still largely unexplored. Here, we show that Tbx1 is co-expressed with the bicoid-like homeodomain transcription factor Pitx2 in secondary heart field cells in the pharyngeal mesenchyme. In situ hybridization studies in Tbx1-1- mouse embryos revealed downregulation of Pitx2 in these cells. To test for a possible genetic interaction, we intercrossed Tbx1+/- and Pitx2+/- mice. Tbx1+/ -; Pitx2+/- mice died perinatally with cardiac defects, including double outlet right ventricle, and atrial and ventricular septal defects, all occurring with variable penetrance. An enhancer located between exons 4 and 5 in which a putative half site was identified near an Nkx2.5-binding site regulates asymmetric expression of Pitx2. We show using in vitro studies that Tbx1 binds to this site and activates the Pitx2 enhancer with the synergistic action of Nkx2.5. The results presented in this study unravel a novel Tbx1-Pitx2 pathway linking Tbx1 to asymmetric cardiac morphogenesis.

Original languageEnglish (US)
Pages (from-to)1565-1573
Number of pages9
JournalDevelopment
Volume133
Issue number8
DOIs
StatePublished - Apr 2006

Fingerprint

Morphogenesis
22q11 Deletion Syndrome
Transcription Factors
Double Outlet Right Ventricle
DiGeorge Syndrome
Atrial Heart Septal Defects
Penetrance
Ventricular Heart Septal Defects
Mesoderm
In Situ Hybridization
Exons
Down-Regulation
Embryonic Structures
Binding Sites

Keywords

  • Cardiac defects
  • Heart
  • Pitx2
  • Secondary heart field
  • Tbx1

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. / Nowotschin, Sonja; Liao, Jun; Gage, Philip J.; Epstein, Jonathan A.; Campione, Marina; Morrow, Bernice E.

In: Development, Vol. 133, No. 8, 04.2006, p. 1565-1573.

Research output: Contribution to journalArticle

Nowotschin, S, Liao, J, Gage, PJ, Epstein, JA, Campione, M & Morrow, BE 2006, 'Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field', Development, vol. 133, no. 8, pp. 1565-1573. https://doi.org/10.1242/dev.02309
Nowotschin, Sonja ; Liao, Jun ; Gage, Philip J. ; Epstein, Jonathan A. ; Campione, Marina ; Morrow, Bernice E. / Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. In: Development. 2006 ; Vol. 133, No. 8. pp. 1565-1573.
@article{2244da7e352245e09e30e35b3ae55619,
title = "Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field",
abstract = "Individuals with 22q11 deletion syndrome (22q11DS; DiGeorge/ velo-cardio-facial syndrome) have multiple congenital malformations, including cardiovascular defects. Most individuals with this syndrome possess 1.5-3.0 Mb hemizygous 22q11.2 deletions. The T-box transcription factor TBX1, lies within the nested 1.5 Mb interval and is a strong candidate for its etiology. Inactivation of Tbx1 in the mouse results in neonatal lethality owing to the presence of a single cardiac outflow tract. One important goal is to understand the molecular pathogenesis of cardiovascular defects in this syndrome. However, the molecular pathways of Tbx1 are still largely unexplored. Here, we show that Tbx1 is co-expressed with the bicoid-like homeodomain transcription factor Pitx2 in secondary heart field cells in the pharyngeal mesenchyme. In situ hybridization studies in Tbx1-1- mouse embryos revealed downregulation of Pitx2 in these cells. To test for a possible genetic interaction, we intercrossed Tbx1+/- and Pitx2+/- mice. Tbx1+/ -; Pitx2+/- mice died perinatally with cardiac defects, including double outlet right ventricle, and atrial and ventricular septal defects, all occurring with variable penetrance. An enhancer located between exons 4 and 5 in which a putative half site was identified near an Nkx2.5-binding site regulates asymmetric expression of Pitx2. We show using in vitro studies that Tbx1 binds to this site and activates the Pitx2 enhancer with the synergistic action of Nkx2.5. The results presented in this study unravel a novel Tbx1-Pitx2 pathway linking Tbx1 to asymmetric cardiac morphogenesis.",
keywords = "Cardiac defects, Heart, Pitx2, Secondary heart field, Tbx1",
author = "Sonja Nowotschin and Jun Liao and Gage, {Philip J.} and Epstein, {Jonathan A.} and Marina Campione and Morrow, {Bernice E.}",
year = "2006",
month = "4",
doi = "10.1242/dev.02309",
language = "English (US)",
volume = "133",
pages = "1565--1573",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "8",

}

TY - JOUR

T1 - Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field

AU - Nowotschin, Sonja

AU - Liao, Jun

AU - Gage, Philip J.

AU - Epstein, Jonathan A.

AU - Campione, Marina

AU - Morrow, Bernice E.

PY - 2006/4

Y1 - 2006/4

N2 - Individuals with 22q11 deletion syndrome (22q11DS; DiGeorge/ velo-cardio-facial syndrome) have multiple congenital malformations, including cardiovascular defects. Most individuals with this syndrome possess 1.5-3.0 Mb hemizygous 22q11.2 deletions. The T-box transcription factor TBX1, lies within the nested 1.5 Mb interval and is a strong candidate for its etiology. Inactivation of Tbx1 in the mouse results in neonatal lethality owing to the presence of a single cardiac outflow tract. One important goal is to understand the molecular pathogenesis of cardiovascular defects in this syndrome. However, the molecular pathways of Tbx1 are still largely unexplored. Here, we show that Tbx1 is co-expressed with the bicoid-like homeodomain transcription factor Pitx2 in secondary heart field cells in the pharyngeal mesenchyme. In situ hybridization studies in Tbx1-1- mouse embryos revealed downregulation of Pitx2 in these cells. To test for a possible genetic interaction, we intercrossed Tbx1+/- and Pitx2+/- mice. Tbx1+/ -; Pitx2+/- mice died perinatally with cardiac defects, including double outlet right ventricle, and atrial and ventricular septal defects, all occurring with variable penetrance. An enhancer located between exons 4 and 5 in which a putative half site was identified near an Nkx2.5-binding site regulates asymmetric expression of Pitx2. We show using in vitro studies that Tbx1 binds to this site and activates the Pitx2 enhancer with the synergistic action of Nkx2.5. The results presented in this study unravel a novel Tbx1-Pitx2 pathway linking Tbx1 to asymmetric cardiac morphogenesis.

AB - Individuals with 22q11 deletion syndrome (22q11DS; DiGeorge/ velo-cardio-facial syndrome) have multiple congenital malformations, including cardiovascular defects. Most individuals with this syndrome possess 1.5-3.0 Mb hemizygous 22q11.2 deletions. The T-box transcription factor TBX1, lies within the nested 1.5 Mb interval and is a strong candidate for its etiology. Inactivation of Tbx1 in the mouse results in neonatal lethality owing to the presence of a single cardiac outflow tract. One important goal is to understand the molecular pathogenesis of cardiovascular defects in this syndrome. However, the molecular pathways of Tbx1 are still largely unexplored. Here, we show that Tbx1 is co-expressed with the bicoid-like homeodomain transcription factor Pitx2 in secondary heart field cells in the pharyngeal mesenchyme. In situ hybridization studies in Tbx1-1- mouse embryos revealed downregulation of Pitx2 in these cells. To test for a possible genetic interaction, we intercrossed Tbx1+/- and Pitx2+/- mice. Tbx1+/ -; Pitx2+/- mice died perinatally with cardiac defects, including double outlet right ventricle, and atrial and ventricular septal defects, all occurring with variable penetrance. An enhancer located between exons 4 and 5 in which a putative half site was identified near an Nkx2.5-binding site regulates asymmetric expression of Pitx2. We show using in vitro studies that Tbx1 binds to this site and activates the Pitx2 enhancer with the synergistic action of Nkx2.5. The results presented in this study unravel a novel Tbx1-Pitx2 pathway linking Tbx1 to asymmetric cardiac morphogenesis.

KW - Cardiac defects

KW - Heart

KW - Pitx2

KW - Secondary heart field

KW - Tbx1

UR - http://www.scopus.com/inward/record.url?scp=33646706385&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646706385&partnerID=8YFLogxK

U2 - 10.1242/dev.02309

DO - 10.1242/dev.02309

M3 - Article

VL - 133

SP - 1565

EP - 1573

JO - Development (Cambridge)

JF - Development (Cambridge)

SN - 0950-1991

IS - 8

ER -