2006/02/22 by Stephanie M. Ware, Karine G. Harutyunyan, John W. Belmont
Biochemistry, Genetics and Molecular Biology · #Congenital heart defects research #Developmental Biology and Gene Regulation #Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
paper · doi:10.1002/dvdy.20719
openalex publication_date 2006/02/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The complex cardiac defects that occur in heterotaxy result from abnormal left-right patterning. Mutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy, HTX1. We previously have generated a targeted deletion of the murine Zic3 locus and demonstrated that these knockout mice correctly model HTX1. Fifty percent of Zic3 null embryos have cardiac looping anomalies at embryonic day 10.5 to 14.5, with ventral looping and sinistral looping as the predominant phenotypes. The penetrance of these phenotypes is increased in mice that are also haploinsufficient for Nodal. Zic3(+/-); Nodal (+/-) compound heterozygous mice are born in significantly reduced numbers (P=0.0001), indicating a genetic interaction between the loci. Furthermore, an upstream Nodal enhancer is responsive to Zic3 in both Xenopus and mouse. These studies provide evidence that Zic3 interacts genetically with Nodal in left-right patterning and subsequent cardiac development and delineate a critical Zic3-responsive enhancer required for mediating Nodal expression at the node.