Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

摘要: Mutations in Notch2, Jagged1 or homologs of the Hairy-related transcriptional repressor Hey2 cause congenital malformations involving non-chamber atrioventricular canal (AVC) and inner curvature (IC) regions heart, but underlying mechanisms have not been investigated. By manipulating signaling directly within developing chick we demonstrated that Hey1 initiate a cascade delimits AVC IC regions. Specifically, misactivation Notch2 signaling, misexpression either Hey2, repressed Bmp2. Because Jagged (also known as Serrate non-mammalian species) ligands were found to be present prospective chamber myocardium, these data support model Hey proteins progressive restriction Bmp2 expression IC, where it is essential for differentiation. Misactivation inhibition specifically induced inhibited Hey1, respectively, manipulations did affect implicating direct mediator Notch2. has shown induce Tbx2, Tbx2 both Hey2. therefore, envisaged constitute feedback loop sharpens border with by delimiting gene Analysis loss-of-function phenotype mouse embryos homozygous targeted disruption revealed an expanded domain Similarly, zebrafish gridlock (Hey2 homolog) mutant showed ectopic Bmp4, which normally marks myocardium this species. Thus, pathway regulation cardiac Bmp appears evolutionarily conserved mechanism delimit fate, provides potential mechanistic explanation caused mutations Serrate/Jagged1 Notch components.