English (United Kingdom)

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Congenital heart defects affect at least 0.8% of newborn children and are a major cause of lethality prior to birth. Malformations of the arterial pole are particularly frequent. The myocardium at the base of the pulmonary trunk and aorta and the arterial tree associated with these great arteries are derived from splanchnic mesoderm of the second heart field (SHF), an important source of cardiac progenitor cells. These cells are controlled by a gene regulatory network that includes  Fgf8 ,  Fgf10  and  Tbx1. Prdm1  encodes a transcriptional repressor that we show is also expressed in the SHF. In mouse embryos, mutation of  Prdm1  affects branchial arch development and leads to persistent  truncus arteriosus  (PTA), indicative of neural crest dysfunction. Using conditional mutants, we show that this is not due to a direct function of Prdm1 in neural crest cells. Mutation of  Prdm1  in the SHF does not result in PTA, but leads to arterial pole defects, characterized by mis-alignment or reduction of the aorta and pulmonary trunk, and abnormalities in the arterial tree, defects that are preceded by a reduction in outflow tract size and loss of caudal pharyngeal arch arteries. These defects are associated with a reduction in proliferation of progenitor cells in the SHF. We have investigated genetic interactions with  Fgf8  and  Tbx1 , and show that on a  Tbx1  heterozygote background, conditional  Prdm1  mutants have more pronounced arterial pole defects, now including PTA. Our results identify  PRDM1  as a potential modifier of phenotypic severity in  TBX1  haploinsufficient DiGeorge syndrome patients.

human molecular genetics

Prdm1  functions in the mesoderm of the second heart field, where it interacts genetically with  Tbx1 , during outflow tract morphogenesis in the mouse embryo