Abstract
The bone morphogenetic protein (Bmp) signaling pathway and the basic helix–loop–helix (bHLH) transcription factor Hand1 are known key regulators of cardiac development. In this study, we investigated the Bmp signaling regulation of Hand1 during cardiac outflow tract (OFT) development. In Bmp2 and Bmp4loss-of-function embryos with varying levels of Bmp in the heart, Hand1 is sensitively decreased in response to the dose of Bmp expression. In contrast, Hand1 in the heart is dramatically increased in Bmp4 gain-of-function embryos. We further identified and characterized the Bmp/Smad regulatory elements in Hand1. Combined transfection assays and chromatin immunoprecipitation (ChIP) experiments indicated that Hand1 is directly activated and bound by Smads. In addition, we found that upon the treatment of Bmp2 and Bmp4, P19 cells induced Hand1 expression and favored cardiac differentiation. Together, our data indicated that the Bmp signaling pathway directly regulates Hand1 expression in a dose-dependent manner during heart development.
Highlights
Congenital heart defects (CHDs) are the most common birth defects, with an estimated prevalence of 1% in newborns [1]
In the canonical bone morphogenetic protein (Bmp) pathway, Bmp ligands such as Bmp2 and Bmp4 bind to their dual-specificity kinase and heterodimeric receptor complex, consisting of type I and type II receptors, which phosphorylates downstream receptor-regulated Smads (R-Smads), i.e., Smad1, Smad5, and Smad8 (Smad1/5/8) [6,7]
Bmp2−/−; Bmp4+/− (Figure 1B) and Bmp2+/−; Bmp4−/− (Figure 1C) mutant embryos had a dramatic decrease in Hand1 expression in the outflow tract (OFT)
Summary
Congenital heart defects (CHDs) are the most common birth defects, with an estimated prevalence of 1% in newborns [1]. Cardiac outflow tract (OFT) defects are the most common. The development of the OFT involves interactions and coordination between two types of progenitor pools: second heart field (SHF) progenitors and cardiac neural crest cells (NCCs), regulated by a complex, fine-tuned molecular regulatory network [2,3]. The phospho-R-Smads form an oligomeric complex with Smad and translocate into the nucleus to regulate the expression of downstream genes. The highly conserved Bmp signaling pathway is essential for heart development [8,9], including OFT formation [10,11,12]. Mouse models with Bmp signaling disruptions result in embryonic lethality and CHDs [13,14,15,16,17], as evidenced by
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
