Open AccessFoxf Genes Integrate Tbx5 and Hedgehog Pathways in the Second Heart Field for Cardiac Septation
Author(s) -
Andrew D. Hoffmann,
Xinan Yang,
Ozanna Burnicka-Turek,
Joshua D. Bosman,
Xiaomeng Ren,
Jeffrey D. Steimle,
Steven A. Vokes,
Andrew P. McMahon,
Vladimir V. Kalinichenko,
Ivan P. Moskowitz
Publication year - 2014
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1004604
Subject(s) - gli1 , biology , gli3 , hedgehog , hedgehog signaling pathway , transcription factor , enhancer , gene regulatory network , haploinsufficiency , genetics , regulation of gene expression , microbiology and biotechnology , chromatin , heart development , sonic hedgehog , gene , gene expression , repressor , phenotype , embryonic stem cell
The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo . GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro . This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5 , and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation.