Genes Integrate and Hedgehog Pathways in the Second Heart Field for Cardiac Septation

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Atrioventricular septal defects (AVSDs) are a common severe class of congenital heart defects. Recent work demonstrates that events in the second heart field (SHF) progenitors, rather than in the heart, drive atrioventricular (AV) septation. Our laboratory has shown that both Hedgehog signaling and the T-box transcription factor, Tbx5, are required in the SHF for AV septation. To understand the molecular underpinnings of the AV septation process we investigated SHF Hedgehog-dependent gene regulatory networks. Transcriptional profiling and chromatin interaction assays identified the Forkhead box transcription factors Foxf1a and Foxf2 as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused AVSDs in mice, demonstrating the biological relevance of this pathway. We identified a cis-regulatory element at Foxf1a that bound TBX5 and Hedgehog transcriptional regulators GLI1 and GLI3 in-vivo. Furthermore, TBX5 and Gli1 co-activate transcription of the identified cis-regulatory element in-vitro. The enhancer is expressed primarily in the pSHF in-vivo, where Tbx5 and Gli1 expression overlap. Our findings implicate Foxf1a and Foxf2 in AV septation and establish Tbx5 and Hedgehog signaling upstream of Foxf genes in a gene regulatory network for cardiac septation.

Vyšlo v časopise: Genes Integrate and Hedgehog Pathways in the Second Heart Field for Cardiac Septation. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004604
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004604

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